The Centers for Disease Control and Prevention estimate that 800,000 to 900,000 Americans live with HIV disease (HIVD) and that it is transmitted to 40,000 others annually. Biomedical research has focused on finding a cause and cure, including early detection techniques and pharmacologic therapies to extend life. Meanwhile, persons with HIVD continue to face multiple challenges as they live with symptoms and the effects of treatment modalities that affect their quality of life. The purpose of this investigation was to identify and explore relations among physical activity (PA), social support, and health-related quality of life (HRQOL) in persons with HIVD who were living in community settings. Findings indicated a significant inverse correlation between participant's HRQOL and meeting moderate or vigorous PA recommendations from Healthy People 2010, but weekly frequency of participating in at least 30 min of moderate or vigorous PA was significantly (r = .49, p < . 01) correlated with HRQOL. Friend social support and weekly frequency of PA accounted for 37% of the variance in HRQOL in a regression analysis.