We examined how two critical constructs, health beliefs and sensation seeking, influence combination antiretroviral therapy adherence in HIV+ African Americans, and whether these factors mediate the association between age and adherence. Two-hundred-and-eighty-six HIV+ African Americans participated in this observational study. Path analyses revealed that higher levels of a specific health belief, perceived utility of treatment, and lower levels of a sensation-seeking component, Thrill and Adventure Seeking, directly predicted optimal adherence. The influence of age on adherence was partially mediated by lower Thrill and Adventure Seeking levels. Depression predicted adherence via perceived utility of treatment and Thrill and Adventure Seeking, whereas current substance abuse and dependence did via Thrill and Adventure Seeking. Poorer neurocognitive function had a direct, adverse effect on adherence. Our findings suggest that supporting the development of more positive perceptions about HIV treatment utility may help increase medication adherence among African Americans. This may be particularly relevant for those with higher levels of depression symptoms, which was directly associated with negative perceptions about treatment. Additionally, clinicians can assess sensation-seeking tendencies to help identify HIV+ African Americans at risk for suboptimal adherence. Compensatory strategies for medication management may help improve adherence among HIV+ individuals with poorer neurocognitive function.