HIV medication adherence remains a challenge and limits the degree to which treatment benefit can be maximized. This study tested an explanatory model of HIV medication adherence using a social problem-solving (SPS) framework. Associations of SPS with adherence are hypothesized to be direct and/or indirect via psychological health. HIV+ adults were interviewed using validated measures of SPS, psychological health, and antiretroviral therapy (ART) medication adherence. Structural equation modeling (SEM) techniques were used to test hypothesized relationships and to evaluate overall fit of the model to the data. SEM supported an indirect association (but not direct) of SPS on adherence via psychological health among the 545 HIV+ adults included in the analyses. Overall, the findings resulted in a model of adherence that offered very good fit to the data and correctly classified 97% of the cases as adherent versus nonadherent. Results support the use of SPS as a conceptual framework for understanding adherence to ART. Findings offer rationale and direction for SPS interventions to enhance adherence by improving psychological health. Such approaches, if effective, have the potential to positively impact psychological well being and adherence, thereby maximizing clinical benefit from treatment, which is linked to lower mortality from AIDS.