Strict medication adherence is integral to the success of highly active antiretroviral therapies (HAART) in patients with HIV. Research has examined several predictors of adherence, but few studies have examined the association between current smoking, which is highly prevalent among people living with HIV, and medication adherence; moreover, no study has examined the mediating role of depressive symptoms, which may influence both smoking and adherence. Therefore, we recruited 168 patients who were prescribed HAART and assessed viral load, CD4+ count, cigarette smoking, past week and 3-month medication adherence, and depressive symptoms. Results showed that 70% smoked at least one cigarette per day. As predicted, smoking was associated with poorer past week and 3-month adherence, and more depressive symptoms. Regression analyses provided partial support for the hypothesis that depressive symptoms mediated nonadherence among smokers. We conclude that future smoking cessation interventions with this population should target medical adherence and depression as intervention components.