In 2001, Barrera moved up in weight division. On April 7, he handed British boxer Naseem Hamed his first and only loss for the lineal featherweight championship by a twelve-round decision. Before the fight, Hamed was a 3 to 1 betting favorite in Las Vegas. Hamed could not hit Barrera with his trademark lefts as Barrera circled to his left and worked both head and body. Barrera was not a fan of Hamed's antics and responded to Hamed's punches during clinches. On one occasion early in the fight, Hamed grabbed Barrera and they both fell to the ground where Barrera threw a right jab, leading to a warning from referee Joe Cortez. In the 12th and final round Barrera trapped Hamed in a full nelson and forced his head into the turnbuckle, resulting in a point deducted by referee Joe Cortez. Ultimately, Barrera threw more, harder punches and more impressive combinations than Hamed throughout the course of the fight. Barrera was awarded the victory via a unanimous decision, with the scorecards reading 115–112, 115–112, 116–111 and won the lineal and IBO featherweight titles. On September 8, 2001, he defeated former champion Enrique Sánchez by sixth-round TKO.