OBJECTIVE: To evaluate cognitive-behavioral therapy to enhance medication adherence and reduce depression (CBT-AD) in individuals with HIV. DESIGN: A two arm, randomized, controlled, cross-over trial comparing CBT-AD to enhanced treatment as usual only (ETAU). ETAU, which both groups received, included a single-session intervention for adherence and a letter to the patient's provider documenting her or his continued depression. The intervention group also received 10 to 12 sessions of CBT-AD. MAIN OUTCOME MEASURES: Adherence to antiretroviral therapy as assessed by Medication Event Monitoring Systems (MEMs) and depression as assessed by blinded structured evaluation. RESULTS: At the acute outcome assessment (3-months), those who received CBT-AD evidenced significantly greater improvements in medication adherence and depression relative to the comparison group. Those who were originally assigned to the comparison group who chose to cross over to CBT-AD showed similar improvements in both depression and adherence outcomes. Treatment gains for those in the intervention group were generally maintained at 6- and 12-month follow-up assessments. By the end of the follow-up period, those originally assigned CBT-AD demonstrated improvements in plasma HIV RNA concentrations, though these differences did not emerge before the cross-over, and hence there were not between-groups differences. CONCLUSIONS: CBT-AD is a potentially efficacious approach for individuals with HIV struggling with depression and adherence. Replication and extension in larger efficacy trials are needed.