Optimal adherence to antiretroviral therapy (ART) is essential for reducing mortality and morbidity in persons living with HIV/AIDS (PLWHA), as well as for reducing the risk of further HIV transmission. While studies have identified psychosocial factors such as lack of social support and poor mental health status as important barriers to optimal ART adherence, few studies have explored the potential of a mediation effect of psychosocial factors on the relationship between social support and optimal ART adherence. This paper assessed whether mental health status mediated the relationship between social support and optimal ART adherence among a cross-sectional sample of 202 persons living with HIV who were recruited from HIV clinical care sites and community-based organizations in Los Angeles County (LAC). Participants completed a survey that included social support items from the Medical Outcome Study: Social Support Survey (MOS-SSS) Instrument, mental health measures from the Medical Outcomes Study Short Form (SF-12), and ART adherence based on self-report. Among those currently taking ART, 61.7% reported having optimal adherence. Social support was significantly associated with a high score on the mental health status scale (AOR =2.90; 95% CI=1.14-5.78) and optimal ART adherence (AOR=1.81; 95% CI=1.81; 95% CI=1.18-2.79). When mental health status was introduced into the model, the association between social support and optimal ART adherence was no longer significant. Our findings suggest the HIV interventions targeting social support to improve ART adherence will likely be most successful if the support bolsters the mental health of the participants. Clearly, better understanding the relationships among social support, mental health, and ART adherence will be critical for development and implementation of future ART adherence interventions.