Physicians are reluctant to treat chronic hepatitis C virus (HCV) infection in active injection drug users (IDUs). An important reason for this is concern about reinfection after successful treatment. However, little is known about this apparent risk; because of lack of protective immunity, reinfection with HCV seems possible. Here, I discuss several cases of probable reinfection in IDUs, 2 of which occurred during or after successful treatment for HCV infection. In a Norwegian trial, 69 IDUs who had abstained from drug use for >or=6 months were treated for HCV infection; of these, 27 tested negative for HCV RNA at 6 months of follow-up (sustained virological response). At 5 years of follow-up, 9 (33%) of the 27 IDUs with sustained virological response had returned to drug use, but only 1 case of reinfection was observed. In another study, 395 subjects with sustained virological response were followed with yearly testing for HCV RNA. Although injection drug use was the route of HCV transmission in 40% of the subjects, only 7 (2%) experienced a late relapse of HCV infection. It has not been determined whether any of these cases were actual reinfections. Available data suggest that the rate of long-term response to treatment for HCV infection is excellent in IDUs.