Goals of this study were to examine the frequency of depression and related constructs of suicidal ideation and hopelessness in a sample of homeless older adolescents and their associations with behaviors that may increase the risk of sexually transmitted disease (STD). Diagnostic interviews and blood/urine samples were obtained from 523 homeless adolescents (mean age=17·8). Overall, 12·2 per cent had a current DSM-IV diagnosis of major depression and 6·5 per cent had dysthymia, with higher rates for female and older participants. Depression appeared to precede rather than follow homelessness and was associated with biologically verified STDs (in older participants), infrequent condom use, a non-heterosexual orientation (in older participants), and lifetime homosexual experience. Unlike depression, suicidal ideation and hopelessness were associated with higher rates of intravenous drug use but lower rates of multiple sex partners and, in young homeless women, less sexual coercion. Depression is frequent in homeless older adolescents and has a complex association with STD-related behaviors.