BACKGROUND: There is a lack of effective behavioral interventions for HIV-positive injection drug users (IDUs). We sought to evaluate the efficacy of an intervention to reduce sexual and injection transmission risk behaviors and to increase utilization of medical care and adherence to HIV medications among this population. METHODS: HIV-positive IDUs (n=966) recruited in 4 US cities were randomly assigned to a 10-session peer mentoring intervention or to an 8-session video discussion intervention (control condition). Participants completed audio computer-assisted self-interviews and had their blood drawn to measure CD4 cell count and viral load at baseline and at 3-month (no blood), 6-month, and 12-month follow-ups. RESULTS: Overall retention rates for randomized participants were 87%, 83%, and 85% at 3, 6, and 12 months, respectively. Participants in both conditions reported significant reductions from baseline in injection and sexual transmission risk behaviors, but there were no significant differences between conditions. Participants in both conditions reported no change in medical care and adherence, and there were no significant differences between conditions. CONCLUSIONS: Both interventions led to decreases in risk behaviors but no changes in medical outcomes. The characteristics of the trial that may have contributed to these results are examined, and directions for future research are identified.