BACKGROUND AND OBJECTIVES: Middle-aged and older adults with human immunodeficiency virus (HIV) are at risk for decreased health-related quality of life (HRQoL), which may be improved by engaging in leisure activities. We examined associations between HRQoL and participation in cognitive, physical, social, and passive leisure activities, and whether depressive symptoms mediated these relationships. Wilson and Cleary's conceptual model of HRQoL guided this study. RESEARCH DESIGN AND METHODS: In this cross-sectional observational study, we enrolled 174 adults living with HIV aged 40 and older (M = 51.3, SD = 7.03). Participants completed assessments of leisure activities, depressive symptoms, and HRQoL. Data were analyzed using Spearman's rho correlations, hierarchal multiple regression, and mediation analyses. RESULTS: Greater engagement in physical activities was associated with higher physical HRQoL (b = 2.02, p < .05). Greater engagement in social activities was associated with both higher physical (b = 1.44, p < .05) and mental HRQoL (b = 1.95, p < .01). However, all associations between leisure activities and HRQoL were fully attenuated by depressive symptoms. Cognitive and passive leisure activities were not significantly correlated with HRQoL. Mediation analyses confirmed that depressive symptoms were the mediator mechanism by which social activities affected mental and physical HRQoL. DISCUSSION AND IMPLICATIONS: More frequent engagement in physical and social leisure activities is associated with better HRQoL, and social leisure activities improve HRQoL via their impact on mood. Interventions to increase leisure activities, especially among people living with HIV who have poorer affective functioning, may be the most effective approach to improving HRQoL.