The success of highly active antiretroviral therapy (HAART) among persons living with HIV is largely dependent on strict medication adherence. Recent research suggests that alcohol and other drug use (AOD) may be an important barrier to HAART adherence. In this study, we examined the impact of AOD on HAART adherence as well as the moderating effects of general and medication-specific social support. The data were collected as part of a longitudinal randomized control trial with 224 HIV-positive patients at an HIV primary care clinic in the northwestern United States. Findings indicated that AOD use was negatively associated with HAART adherence and that medication-specific (but not general) social support moderated the AOD-adherence association at 3 (but not at 6 or 9) months. Results indicate the importance of medication-specific social support to treat comorbid AOD use and HIV; implications for future research and intervention programs for HIV-positive AOD users are discussed.