We undertook a retrospective medical chart review of HIV-infected adolescents referred to a Southern US urban comprehensive adolescent HIV clinic between 1992 and 2003 to describe the psychosocial profile of adolescents infected with HIV via high-risk behaviours.Ninety-one adolescents (59 females, 32 males, 95% African-American, median age 17 years) were identified. Common reasons for initial HIV testing included routine prenatal screening (20%), clinical symptoms suggestive of HIV (20%), and recognized risk-related behaviours (20%). Findings included a history of unstable housing in the previous year (27%), running away (29%), knowing someone with HIV (36%), parental substance abuse (reported by youth, 46%), parental abandonment/neglect (30%), high substance use rates (marijuana 33%, tobacco 27%), current/prior STDs (60%), and involvement with the juvenile justice system or incarceration (41%). Sexual abuse/assault was reported by 41%. Previous depression was reported in 15% with approximately half reporting prior hospitalization. An additional 12% of the cohort had current clinical depressive symptoms. We conclude that infections with HIV via high-risk behaviours during adolescence occur in youth with multiple psychosocial stressors. Targeted prevention efforts to reduce these underlying stressors may decrease new adolescent infection. HIV-infected youth are best served in a comprehensive care environment with immediate access to medical care, social work, and psychology/psychiatry services.