Highly active antiretroviral therapy (HAART) has reduced the incidence of death in HIV-infected patients but various rates of survival have been reported due to the infection with hepatitis C virus (HCV) and the use of injecting drugs (IDU). A survival analysis was performed to estimate and compare the death rates in HIV-positive patients infected by IDU and/or positive for HCV antibodies in the pre-HAART and HAART periods in Lyon (France) between 1992 and 2002. Patients were stratified into four groups (G): HCV-/IDU-(G1), HCV+/IDU-(G2), HCV+/IDU-(G3), HCV+/IDU+ (G4) and adjusted death rates in the pre-HAART era (< 1996) and the HAART era (> or = 1996) were compared. The aHR of progression to death was 1.05 (95% CI 0.75-1.47, P = 0.75) for G2, 1.09 (95% CI 0.54-2.22, P = 0.81) for G3 and 0.90 (95% CI 0.65-1.24, P =0.51) for G4 compared with G1 in the pre-HAART era. The aHR of progression to death was 0.76 (95% CI 0.28-2.08, P = 0.59) for G2, 1.23 (95% CI 0.17-8.86, P = 0.84) for G3 and 2.90 (95% CI 1.62-5.20, P < 0.001) for G4, compared with G1 in the HAART era. HAART management of HCV+/IDU+ patients needs to be optimized for them to achieve a similar benefit as observed among other individuals.