On December 17, 2005 he lost his title for the third time — in controversial fashion, as usual — to Nicolay Valuev. Ruiz lost a rematch for the vacant WBA Heavyweight title with Valuev on August 30th, 2008.
After Lennox Lewis defeated Evander Holyfield for the Undisputed (i.e., WBC + IBF + WBA) World Heavyweight Championship in late 1999, the WBA ordered Lewis to defend the title against Ruiz, its #1-ranked contender, but Lewis refused. Though he had been undefeated since a loss against David Tua in 1996, the level of competition Ruiz had been facing was suspect.
Ruiz and his management sued, claiming that WBA rules entitled him to a title shot. A judge agreed, but rather than face Ruiz in a bout that was seen as commercially unattractive, Lewis instead fought Michael Grant, considered to be a very worthy contender at the time. After learning of this, the judge decreed that upon entering the ring against Grant on April 29, 2000, Lewis would automatically forfeit the WBA Title.
Ruiz fought former champion Holyfield to fill the vacancy on August 12, 2000, losing by unanimous decision (this result made Holyfield the first to win a world heavyweight title on four separate occasions). Many observers and boxing reporters felt that the underdog Ruiz had done enough to win. Due to this controversial decision, the WBA ordered an immediate rematch in early 2001, and Ruiz won the WBA Championship in a slightly less-close unanimous decision. He defended the title twice: a draw in a third match against Holyfield, and a 10th-round victory over Kirk Johnson (disqualified for repeatedly punching below the waist). Ruiz was accused in both the second Holyfield fight and the Johnson fight of faking low blows that actually seemed to be closer to his beltline than his groin. On March 1, 2003 at Caesars Palace in Las Vegas, Nevada, Ruiz’s first reign as champion ended—against a light heavyweight whom he outweighed by over 30 lb. He lost a unanimous decision to Roy Jones, Jr. Ruiz blamed the referee for the loss, claiming that he "did not let me fight my fight".
In defeating Ruiz, Jones joined Michael Spinks and Michael Moorer as the only light-heavyweight titlists to later win a world heavyweight title. Jones was also only the second former world middleweight champion to win a heavyweight title (the first being Bob Fitzsimmons, who beat "Gentleman" Jim Corbett on March 17, 1897).
Vitali Klitschko refused contractual negotiations for the Rahman match, opposed to fighting for an illegitimate championship. The WBA then turned to David Tua, its #3 contender. While Tua initially agreed to fight Rahman, he later pulled out of the bout, too. Ruiz, whom Tua had beaten in 1996 — but as the #5 contender, was the highest-ranked fighter still interested — agreed to fight Rahman, a former WBC / IBF world heavyweight champion who had won and lost those belts to Lennox Lewis (by KO) in 2001.
On December 13, 2003, Ruiz defeated Rahman by unanimous decision, earning him the first-ever WBA Interim world Heavyweight Title. On February 20, 2004, Roy Jones, Jr. advised the WBA that he would return to the light-heavyweight division, vacating its heavyweight championship. The WBA then removed the "interim" tag from Ruiz’s championship status, declaring his victory over Rahman good enough to warrant being the official WBA world Heavyweight Champion.
On April 17, 2004, Ruiz fought the first defense of his second world title. He retained it with an eleventh-round technical knockout of Fres Oquendo at Madison Square Garden. This fight was historic in that it was the first time two Hispanics/Latinos faced each other for a world heavyweight title.
On November 13 of that same year, Ruiz retained the belt with a close unanimous-decision over Polish-American Andrzej Gołota (a.k.a., "Andrew" Golota), although he suffered two knockdowns and a one-point deduction by referee Randy Neumann. But Ruiz managed to win the complete 2nd half of the fight which was enough get the decision.
On April 30, 2005, Ruiz lost the title to James "Lights Out" Toney in Madison Square Garden. However, after Toney failed the post-match drug test (for stanozolol, an anabolic steroid), the New York Athletic Commission suspended him from boxing in the USA for 90 days, and fined him $10,000 (U.S.). The WBA banned the aging (then 36 years-old) Toney from fighting for its heavyweight title for the next two years. This resulted in Toney's win being changed to a "no contest" — basically, a nullification. Ruiz came out of retirement before it was found out that Toney would be suspended and he would be reinstated as champion.

In September 2006 Ruiz announced that he would be managed by Wilfried Sauerland, the very same man who manages Valuev. His former manager Norman Stone retired on December 22nd, 2005, stating that the decision in the loss to Valuev was the last straw, and he would continue to support Ruiz from retirement.
Ruiz followed up the loss to Valuev with a fight against up-and-coming contender Ruslan Chagaev. In a close fight, Chagaev prevailed, taking a split decision with scores of 117-111 and 116-112 for Chagaev, and 115-114 for Ruiz. Chagaev became the mandatory challenger for a shot at Valuev, whom he defeated on April 14, 2007 to claim the heavyweight championship.
Valuev defeated Ruiz by unanimous decision on August 30th. Scores were 114-113, 116-113, and 116-111. The result was initially declared a split decision win for Valuev. The 114-113 score by ringside judge Takeshi Shimakawa was announced in favor of Ruiz. Shimakwa alerted WBA officials after that his score was intended for Valuev. One of the scorecards had the names of the fighters in opposite order, resulting in the confusion.
The decision was once again unpopular with the live crowd as some booed the outcome, much like the first match in December of 2005.