Injection drug users (IDUs) who are in a methadone maintenance therapy program are required to attend their drug treatment clinic on a regular basis for directly observed therapy (DOT). Such programs provide a unique opportunity to administer HAART to HIV-infected persons in this marginalized population in conjunction with their methadone therapy. A prospective observational study was conducted to determine the efficacy of directly observed antiretroviral therapy provided in conjunction with daily observed methadone maintenance therapy. A cohort of 39 patients was enrolled to receive HAART as DOT. At 48 weeks, 51% of antiretroviral-experienced patients and 65% of antiretroviral-naive patients had achieved maximum viral suppression. DOT should therefore be considered a potential option for providing HAART to IDUs, particularly when used in conjunction with methadone maintenance therapy.