He decided to go to the Tour for the first time in his career, where he recorded several top 10 finishes and fourth in the points classification.

He ended the year by being a part of the winning Italian lead-out train for Cipollini in the Road World Championship in Zolder.

Petacchi started the season strongly by winning Trofeo Luis Puig and a stage in both Vuelta Ciclista a la Comunidad Valenciana and Paris–Nice.

He attempted to recreate his 2003 season by participate in the Tour, however it became a disappointment and dropped out on stage 6 due to injuries.

Petacchi started his 2005 season early by winning GP Costa Degli Etruschi and several stages of Vuelta an Andalucia.

He had the better of a mass sprint, beating Danilo Hondo, Thor Hushovd, Stuart O'Grady and Óscar Freire.

In July 2005, Petacchi announced that, following the decision to disband Fassa Bortolo, he would join Domina Vacanze for the 2006 season.

With support from his teammate Erik Zabel, Petacchi was the victor in the mass gallop, with Francesco Chicchi and Óscar Freire rounding up the podium.

[3] After he returned an "Adverse Analytical Finding" (AAF), a higher level than officially allowed of the asthma medication salbutamol, which Petacchi had clearance to use, he was placed on non-active status and missed the 2007 Tour de France.

[13] On 6 May 2008, the World Anti-Doping Agency won its challenge against the Italian national governing body at the Court of Arbitration for Sport.

The court said Petacchi had not intended to cheat and that it was likely that he had inadvertently consumed too much medication, but he had not exercised "utmost caution.

"[14] The case was considered controversial,[15] as it kept Petacchi from starting the Tour de France as he had planned[16] and for the court ruling that he should be suspended despite acknowledging that he had not cheated.

In so doing he was the 1st person to complete the feat since 1999 and the first Italian to win the points classification in the Tour de France since 1968.

However he subsequently expressed a desire to take up an offer from the Omega Pharma–Quick-Step team to ride as a lead-out man for Mark Cavendish, which he said was made to him days after his retirement.

[22] In July 2013 Patrick Lefevere announced that Petacchi would be joining Omega Pharma–Quick-Step from the start of August on a 14-month contract.

[23] On 14 May 2019, Petacchi was named by the French newspaper Le Monde as an alleged client of doctor Mark Schmidt, who administered illegal blood transfusion for the purpose of performance enhancement to athletes in what has become known as Operation Aderlass.