BACKGROUND: Stress management interventions can reduce symptoms of distress as well as modulate certain immune system components in persons infected with human immunodeficiency virus (HIV). These effects may occur in parallel with reductions in hypothalamic-pituitary-adrenal (HPA) axis hormones such as cortisol, which has been related in other work to a down-regulation of immune system components relevant to HIV infection. The present study tested the effects of a multimodal cognitive-behavioral stress management (CBSM) intervention on 24-hour urinary free cortisol levels and distressed mood in symptomatic HIV+ gay men. METHODS: Symptomatic HIV-infected gay men who were randomized to either a 10-week group-based CBSM intervention or a 10-week wait-list period provided psychological responses and urine samples pre-post intervention. RESULTS: Of the 59 participants providing matched questionnaire data, men assigned to CBSM (n = 40) showed significantly lower posttreatment levels of self-reported depressed affect, anxiety, anger, and confusion than those in the wait-list control group (n = 19). Among the 47 men providing urine samples (34 CBSM, 13 controls), those assigned to CBSM revealed significantly less cortisol output as compared to controls. At the individual level, depressed mood decreases paralleled cortisol reductions over this period across the entire sample. CONCLUSION: A time-limited CBSM intervention reduced distress symptoms and urinary free cortisol output in symptomatic HIV+ gay men and greater reductions in some aspects of distress, especially depressed mood, paralleled greater decreases in cortisol over the intervention period. If persisting stressors and depressed mood contribute to chronic HPA axis activation in HIV-infected persons, then interventions such as CBSM, which teaches them to relax, alter cognitive appraisals, use new coping strategies, and access social support resources, may decrease distress and depressed mood and normalize HPA axis functioning.