Adherence to antiretroviral therapy (ART) among HIV-infected individuals is necessary to both individual and public health, and psychosocial problems have independently been associated with poor adherence. To date, studies have not systematically examined the effect of multiple, co-occurring psychosocial problems (i.e., "syndemics") on ART adherence. Participants included 333 HIV-infected individuals who completed a comprehensive baseline evaluation, as part of a clinical trial to evaluate an intervention to treat depression and optimize medication adherence. Participants completed self-report questionnaires, and trained clinicians completed semi-structured diagnostic interviews. ART non-adherence was objectively measured via an electronic pill cap (i.e., MEMS). As individuals reported a greater number of syndemic indicators, their odds of non-adherence increased. Co-occurring psychosocial problems have an additive effect on the risk for poor ART adherence. Future behavioral medicine interventions are needed that address these problems comprehensively, and/or the core mechanisms that they share.