We evaluated the impact of HIV risk practice on immune reconstitution in a prospective cohort of 288 patients (176 former injecting drug users) who maintained complete virus suppression for more than 24 months. Significant differences in CD4 cell counts at 6 and 24 months were detected. Multivariate analysis showed that drug use was an independent predictor of poor immunological recovery. Injection drug abuse impairs short and long-term CD4 cell recovery in HIV-positive patients initiating successful highly active antiretroviral therapy.