Cross-sectional studies to date that examine psychosocial correlates of antiretroviral adherence have insufficiently addressed the challenges of long-term adherence. This longitudinal study examined mental health, substance abuse, and psychosocial predictors of long-term adherence to antiretroviral medications and medical appointments among HIV-seropositive mothers recruited from an infectious disease clinic of a large urban medical center. Individual interviews were conducted at baseline and two follow-up points, 8 to 18 months after enrollment. Based on a model of health behavior, we examined psychiatric and psychosocial predictors of adherence to antiretroviral medications and medical appointments over time. Presence of a psychiatric disorder, negative stressful life events, more household members, and parenting stress were significantly associated with both missed pills and missed medical appointments at follow-up. Baseline substance abuse was associated with missed pills at follow-up and lack of disclosure to family members at baseline was associated with missed medical appointments at follow-up. These findings suggest that interventions that integrate mental health, substance abuse and medical care may be important to improving the medical adherence and health of HIV-seropositive women, particularly in multistressed populations with substantial caregiving and other life demands.