OBJECTIVES: To determine the impact of depression on highly active antiretroviral therapy (HAART) adherence and clinical measures and investigate if selective serotonin reuptake inhibitors (SSRIs) improve these measures. DESIGN: Retrospective cohort study. METHODS: In 2 large health maintenance organizations, we measured the effects of depression (with and without SSRI use) on adherence and changes in viral and immunologic control among HIV-infected patients starting a new HAART regimen. HAART adherence, HIV RNA levels, and changes in CD4 T-cell counts through 12 months were measured. RESULTS: A total of 3359 patients were evaluated; 42% had a depression diagnosis, and 15% used SSRIs during HAART. Depression without SSRI use was associated with significantly decreased odds of achieving > or =90% adherence to HAART (odds ratio [OR] = 0.81, 95% confidence interval [CI]: 0.70 to 0.98; P = 0.03). Depression was associated with significantly lower odds of an HIV RNA level <500 copies/mL (OR = 0.77, 95% CI: 0.62 to 0.95; P = 0.02). Depressed patients compliant with SSRI medication (>80% adherence to SSRI) had HAART adherence and viral control statistically similar to nondepressed HIV-infected patients taking HAART. Comparing depressed with nondepressed HIV-infected patients, CD4 T-cell responses were statistically similar; among depressed patients, those compliant with SSRI had statistically greater increases in CD4 cell responses. CONCLUSIONS: Depression significantly worsens HAART adherence and HIV viral control. Compliant SSRI use is associated with improved HIV adherence and laboratory parameters.