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OBJECTIVE: To estimate the costs, effectiveness, and cost-effectiveness of prevention interventions for out-of-treatment substance abusers at risk for HIV. This is the first cost-effectiveness study of an AIDS intervention that focuses on drug use as an outcome. STUDY DESIGN: We examined data from the North Carolina Cooperative Agreement site (NC CoOp). All individuals in the study were given the revised NIDA standard intervention and randomly assigned to either a longer, more personalized enhanced intervention or no additional intervention. We estimated the cost of each intervention and, using simple means analysis and multiple regression models, estimated the incremental effectiveness of the enhanced intervention relative to the standard intervention. Finally, we computed cost-effectiveness ratios for several drug use outcomes and compared them to a "back-of-the-envelope" estimate of the benefit of reducing drug use. PRINCIPAL FINDINGS: The estimated cost of implementing the standard intervention is $187.52, and the additional cost of the enhanced intervention is $124.17. Cost-effectiveness ratios range from $35.68 to $139.52 per reduced day of drug use, which are less than an estimate of the benefit per reduced drug day. CONCLUSIONS: The additional cost of implementing the enhanced intervention is relatively small and compares favorably to a rough estimate of the benefits of reduced days of drug use. Thus, the enhanced intervention should be considered an important additional component of an AIDS prevention strategy for out-of-treatment substance abusers.