On
January 29, 2006 Rey Mysterio competed in the
Royal Rumble, entering in the number 2 position, and later eliminating
Randy Orton to win the match . By winning the Royal Rumble, Mysterio earned a World Heavyweight title shot at that years
WrestleMania. By lasting over 62 minutes in the match, Mysterio also set a Royal Rumble record for longevity and size.
Rey dedicated his performance at the Royal Rumble to Eddie Guerrero. After his win, he was congratulated by
Chris Benoit, Dean Malenko, Chavo Guerrero and
Rob Van Dam - all close friends and family of Eddie Guerrero.
During the
February 3, 2006 episode of
SmackDown!, an upset Randy Orton interrupted Mysterio's victory speech. Orton challenged Mysterio to a match for his WrestleMania World title shot. As Rey looked upward for guidance on this decision Orton verbally attacked him and the memory of Guerrero, saying "Eddie ain't in heaven, Eddie's 'down there'-- IN HELL!" Mysterio attacked Orton and later accepted the challenge.
At
No Way Out Randy Orton defeated Rey Mysterio while illegally using the ropes to get the pin. Having lost the title shot at WrestleMania 22, Rey went backstage with a few members of Guerrero's close family. However on the next edition of
Smackdown!, the
SmackDown! General Manager
Theodore Long added Rey, making the match a Triple Threat match for the
World Heavyweight Title. At WrestleMania 22, Rey faced off against both Randy Orton and then-World Heavyweight Champion
Kurt Angle. Mysterio won the match by pinning Randy Orton after a combination of "The 619" and "The West Coast Pop" to win his first World Heavyweight Championship.
On the
April 7, 2006 edition of
SmackDown!, Rey Mysterio, who was billed as being an "
underdog champion," made his first World Heavyweight Title defense against Randy Orton. Mysterio went on to retain his title again during a WrestleMania rematch on
SmackDown! against Kurt Angle, three weeks later. The week before the title defense took place saw the start of a feud between then United States Champion John Bradshaw Layfield and Mysterio. The rivalry kicked off after JBL stated he deserved the World Heavyweight title during his celebration of becoming the U.S. Champion.
The feud with JBL saw Mysterio face off against any opponent of JBL's choosing in the three weeks leading up to his title match against Mysterio at
WWE Judgment Day 2006. Mysterio was defeated by
Mark Henry and
The Great Khali in separate non-title matches before facing
RAW's Kane in a match that went to a no contest. Mysterio retained his title against JBL at Judgement Day. JBL lost the US Championship to
Bobby Lashley five days later on SmackDown! after being tricked by Mysterio to take on all comers like he had. This led JBL to vow that if he didn't win his rematch against Mysterio, he would quit
SmackDown!. In the main event of the evening Mysterio won and retained the World Heavyweight Championship, causing JBL to (
kayfabe) leave
SmackDown!, until
ECW One Night Stand, when JBL announced he would return as color commentator (in reality, JBL had lime build up in his liver that forced him to retire from the ring indefinitely).
At One Night Stand, it was revealed that Rey would have to defend his title against ECW wrestler
Sabu. In the weeks leading up to his title defense, Mysterio defeated WWE Cruiserweight Champion Gregory Helms in a Champion vs. Champion match and was defeated by
Rob Van Dam at WWE vs. ECW Head to Head on
June 7, 2006. Immediately after WWE vs. ECW, WWE.com reported that
Paul Heyman approached Mysterio about switching brands to ECW. Rey announced on the
June 9, 2006 edition of
SmackDown! that he would stay "home", on WWE's
SmackDown!. At
One Night Stand, Mysterio (who was wearing a mask with the letters "ECW" written on the back, despite being a face and booed by ECW fans) retained his title in a hard fought match after he and Sabu were ruled unable to continue following a triple jump DDT through a table from Sabu.
Mysterio would later defend his title against Mark Henry. Mysterio won the match, after Chavo Guerrero came to the ring as the referee was down and hit the "World's Strongest Man" with a steel chair. When the referee regained consciousness, Rey had used a trick of Eddie Guerrero's and pretended to be knocked out and left the challenger holding the chair and eventually won via DQ. Mysterio would then start a feud with
King Booker after Booker won a
Battle Royal to become the number one contender for the World Heavyweight Championship. King Booker attacked Rey from behind backstage with the help of Booker's wife Queen Sharmell. The attack was not shown live and was during the beating of Mark Henry by Batista. The footage was aired the week later on SmackDown! and was followed by Mysterio attacking the King and his "court."
This rivalry continued for several weeks and saw Mysterio defeating King Booker's royal court member
William Regal on an edition of
SmackDown!, moments before attacking the challenger and hitting him with a 619 around the steel post. During
Saturday Night's Main Event, Mysterio defeated King Booker in a six man tag match and again days later on
SmackDown! in singles action. At
The Great American Bash, Rey lost the World Heavyweight Championship to King Booker after Chavo Guerrero turned on Rey and hit him with a steel chair. Then on one edition of
SmackDown!, Rey Mysterio challenged
Chavo Guerrero in a I Quit match. In that match, Chavo injured (kayfabe) Mysterio's knee, causing him to take time off wrestling.
Mysterio made a successful in-ring return at
SummerSlam 2007, defeating
Chavo Guerrero with the 619, after Guerrero had obsessed over Mysterio's return, wanting to injure Mysterio again. On the
August 31 edition of
Smackdown!, Mysterio won a "Championship Competition" to become the number 1 contender for the World Heavyweight Championship, defeating
Batista and
Finlay. On the
September 7th edition of
Smackdown, Mysterio had a
I Quit Match with
Chavo Guerrero. Mysterio won the match by hitting Guerrero's knee with a chair repeatedly, winning the match in a similar manner to which Mysterio had been put out of action. Mysterio then began a feud with
The Great Khali which would lead to a match at
Unforgiven where he would face Khali for the World Heavyweight Championship (the match was eventually made a Triple Threat match also involving Batista) but was unsuccessful in capturing the title.. On October 28, he beat Finlay in a Stretcher match (the other two choices being shilleligh on a pole match and No DQ match) at Cyber Sunday.