Directly observed therapy (DOT) is an effective approach for the treatment of tuberculosis among substance users. We have adapted this model to treat human immunodeficiency virus infection. Our experience suggests that community-based, modified DOT should be explored further as a means to treat infectious diseases and chronic medical illnesses for persons with drug dependence; it may be especially pertinent for the treatment of hepatitis C virus infection. DOT can both optimize adherence and provide a way to offer psychosocial support and linkages to social, addiction, psychiatric, and other services, to help address many of the challenges faced by persons with substance abuse disorders.