ObjectiveTo identify the effects of substance abuse status (active, former, and never) on utilization of highly active antiretroviral therapy (HAART), medication adherence, and virologic and immunologic responses to therapy.DesignProspective cohort study of 764 HIV-1–infected patients who attended an urban HIV clinic and participated in a standardized interview.Main Outcome MeasuresPast utilization of HAART, self-reported nonadherence with antiretroviral therapy, and changes in HIV-1 RNA level and CD4+lymphocyte count relative to prior peak and nadir, respectively.ResultsForty-four percent of active drug users failed to utilize HAART compared with 22% of former drug users and 18% of non–drug users (p< .001 for both comparisons). Among participants who were taking antiretroviral therapy when interviewed, active drug users were more likely to report medication nonadherence (34% vs. 24% of nonusers and 17% of former users), had a smaller median reduction in HIV-1 RNA from baseline (0.8 log10copies/ml vs. 1.7 in nonusers and 1.6 in former users), and had smaller median increases in CD4+lymphocyte count from baseline (65 cells/mm3vs. 116 in nonusers and 122 in former users) (p< .05 for all comparisons with active users).ConclusionsActive drug use was strongly associated with underutilization of HAART, nonadherence, and inferior virologic and immunologic responses to therapy, whereas former drug users and non–drug users were similar in all outcomes. Effective strategies are needed that integrate HIV-1 and substance abuse treatments.