© 2015 Wolters Kluwer Health, Inc. All rights reserved. Background: Depression is a major barrier to HIV treatment outcomes. Objective: To test whether antidepressant management decision support integrated into HIV care improves antiretroviral adherence and depression morbidity. Design: Pseudo-cluster randomized trial. Setting: Four US infectious diseases clinics. Participants: HIV-infected adults with major depressive disorder. Intervention: Measurement-based care (MBC)-depression care managers used systematic metrics to give HIV primary-care clinicians standardized antidepressant treatment recommendations. Measurements: Primary-antiretroviral medication adherence (monthly unannounced telephone-based pill counts for 12 months). Primary time-point-6 months. Secondary-depressive severity, depression remission, depression-free days, measured quarterly for 12 months. Results: From 2010 to 2013, 149 participants were randomized to intervention and 155 to usual care. Participants were mostly men, Black, non-Hispanic, unemployed, and virally suppressed with high baseline self-reported antiretroviral adherence and depressive severity. Over follow-up, no differences between arms in antiretroviral adherence or other HIV outcomes were apparent. At 6 months, depressive severity was lower among intervention participants than usual care [mean difference-3.7, 95% confidence interval (CI)-5.6,-1.7], probability of depression remission was higher [risk difference 13%, 95% CI 1%, 25%), and suicidal ideation was lower (risk difference-18%, 95% CI-30%,-6%). By 12 months, the arms had comparable mental health outcomes. Intervention arm participants experienced an average of 29 (95% CI: 1-57) more depression-free days over 12 months. Conclusion: In the largest trial of its kind among HIV-infected adults, MBC did not improve HIV outcomes, possibly because of high baseline adherence, but achieved clinically significant depression improvements and increased depression-free days. MBC may be an effective, resource-efficient approach to reducing depression morbidity among HIV patients.