After weeks of vignettes airing, Sylvain Grenier and Duprée made their first appearance on the April 28, 2003 edition of Raw as La Résistance by attacking Scott Steiner. Steiner had made remarks two weeks earlier comparing France to hell and Grenier and Duprée were offended. La Résistance went on to feud with Scott Steiner and Test, who was forced to be Steiner's tag team partner by Stacy Keibler. La Résistance ended up defeating Steiner and Test at Judgment Day on May 18, 2003 in the team's pay-per-view debut.
On June 15, 2003, La Résistance won the World Tag Team Championship from Kane and Rob Van Dam at Bad Blood, making Duprée the youngest superstar in WWE history to win the World Tag Team Championship at age 19.
The third member of La Résistance, Rob Conway, was originally introduced as an unnamed American serviceman being abused by Grenier and Duprée. When The Dudley Boyz came out to attack La Résistance, they brought Conway into the ring with an American flag. Once the Dudley Boyz had their backs turned, Conway attacked them with the American flag and then tore it off the pole and laid it on top of them. Conway, now renamed to Robért Conway, joined Duprée and Grenier and the trio began carrying the French flag to ringside and singing the French national anthem before their matches. La Résistance dropped the titles to the Dudley Boyz at Unforgiven in a three-on-two handicapped tables match. The trio went on to feud with several tag teams, including the Dudley Boyz, Rosey and The Hurricane, and Garrison Cade and Mark Jindrak.
In October 2003, Grenier suffered a back injury. Duprée and Conway held the tag team together until Grenier returned on the March 15, 2004 edition of Raw. The trio did not last long after that, as Duprée was the first pick in the 2004 Draft Lottery on March 22.
Duprée made his SmackDown! debut on the March 25, 2004 edition of SmackDown! by defeating Billy Kidman. He briefly had a talk show on SmackDown!, called "Cafe de René", but his only guest was Torrie Wilson as the segment was discarded after only one night. For several months, he went for the United States Championship, held by John Cena. After an incident that happened during his "Cafe de René" (the same incident involving Torrie Wilson), Duprée challenged Cena to a title match. The match was granted by the then-SmackDown! General Manager Kurt Angle and it would took place at Judgment Day. Cena retained the title when he pinned Dupree after executing an FU.After losing to Cena, Duprée focused on the WWE Tag Team Championship and eventually won the title with Kenzo Suzuki on September 9, but then lost the championship on the December 9 edition of SmackDown! to Rob Van Dam and Rey Mysterio. This match happened just days before Van Dam and Mysterio were to challenge Duprée and Suzuki at Armageddon. At the pay-per-view, both teams had a rematch with the roles reversed, but Duprée and Suzuki were unable to regain the tag titles.On the March 24, 2005 airing of SmackDown!, he was "sacrificed" by The Undertaker as a message to Randy Orton (regarding their match at WrestleMania 21), when The Undertaker interrupted a match between Duprée and Booker T. The result of the "sacrifice" saw René receiving a Tombstone Piledriver on the steel steps which lead up to the ring. Duprée was taken off television after this, working dark matches until the April 28 edition of SmackDown!, where he was defeated by John Cena. Duprée went back to dark matches and a few Velocity matches until the June 18 edition of Velocity, where Duprée came out calling himself the "French Phenom", defeating Mark Jindrak. The following week on Velocity, Duprée came out with a new look, sporting black trunks with his initials as well as jet black hair and a Dalí-styled goatee.On June 30, Duprée became one of the last minute trades in the 2005 WWE Draft Lottery, which saw him jump from SmackDown! back to Raw. On the July 4 edition of Raw, Duprée redebuted with his French Phenom gimmick and defeated Val Venis on the same night. Duprée began cutting promos using a new quote referring to himself as "Simply Phenomenal". Duprée also began a winning streak against superstars such as The Hurricane, Matt Striker and Tajiri before suffering a near career-ending hernia in mid-September.Once Duprée was cleared to wrestle, WWE sent him back to Ohio Valley Wrestling for training before returning to WWE. In December 2005, however, it was revealed that he was plagued by a recurring hernia. He later underwent surgery for the injury, but it was unsuccessful. Duprée later returned to OVW then to his father's Grand Prix Wrestling, forming a team with his brother Jeff, before wrestling dark matches on the Raw brand.
On the August 8, 2006, episode of ECW on Sci Fi, a promo aired with Duprée, sporting a clean shave and long hair, announcing that he would be debuting for the brand soon. Promos aired throughout the rest of August showing Duprée taking pictures, posing in mirrors, and working out, while claiming he is "the most extreme athlete in ECW history".
Duprée made his ECW debut on September 12, 2006, defeating Balls Mahoney. On the February 20, 2007 edition of ECW, Duprée reformed La Résistance with Sylvain Grenier, but the team's reunion was short lived after Duprée was suspended at the start of March and sent to rehab after violating the Health and Wellness policy.
Duprée returned to the ring at WWE's new developmental territory Florida Championship Wrestling on June 26, 2007 and defeated Steve Madison. However, he was released from his WWE contract on July 26, 2007 by his own request.