Numerous studies have linked social support to better medication adherence among illness groups, but few have examined potential mechanisms for this relationship. Relationships were examined between social support, depression, positive states of mind (PSOM), and medication adherence among HIV positive men who have sex with men (n = 61) and women (n = 29) on highly active antiretroviral therapy. Depression and PSOM were evaluated as potential mediators of the relationship between support and adherence. Cross-sectional data showed that greater social support and PSOM related to better adherence whereas higher depression scores related to nonadherence. PSOM partially mediated the relationship between social support and adherence. PSOM may be an important mechanism through which social support is related to better medication adherence in this population.