Depression and human immunodeficiency virus disease are common co-occurring conditions among youth living with human immunodeficiency virus/AIDS. Depression serves as a risk factor for contracting the disease and for nonadherence to medications and adherence to safe sex practices. Although new infections are decreasing nationally, subpopulations of youths continue to have the highest rates of new infections, specifically ethnic and sexual minority youths. Depression contributes to poor health outcomes for youths with human immunodeficiency virus disease. Evidence-based psychotherapy and pharmacotherapy for depression are effective treatments. Integrated care with medical and mental health provides the best care for this population of youth.