Research has established a link between perceived social support and health-related quality of life (HRQOL) among persons living with HIV/AIDS. However, little is known about the ways through which social support influences HRQOL. This study examined the direct and indirect effects of perceived social support on physical and mental HRQOL in a sample of 602 adults living with HIV in Ontario, Canada. Participants completed the Medical Outcomes Study-HIV (MOS-HIV) health survey, the MOS-HIV Social Support Scale (MOS-HIV-SSS), and the Center for Epidemiological Studies Depression-Revised scale. Data on demographic and clinical characteristics were also collected. The direct and indirect effects of social support on the two MOS-HIV HRQOL summary measures, that is, physical health summary (PHS) and mental health summary (MHS), were estimated in multiple linear regression analyses. Perceived social support had significant direct effects on PHS (B=0.04, p<0.01) and MHS (B=0.05, p<0.01). It also had significant indirect effect on both PHS (B=0.04, p<0.01) and MHS (B=0.11, p<0.01), mediated by depressive symptoms. Interventions that enhance social support have the potential to contribute to better HRQOL either directly or indirectly by decreasing the deleterious effect of depressive symptoms on HRQOL.