Little has been written about the treatment of substance use disorders among seropositive HIV patients or high-risk seronegative substance abusers. Demographic and clinical characteristics, along with treatment issues, were examined based on experience with 18 patients in a substance abuse program in a university medical center (3 AID, 3 ARC, 9 seropositive only, and 3 seronegative high risk). Scores on a substance abuse rating scale were extremely high. Most of them abused three or more different substances, had used drugs parenterally, had more than 50 sex partners, and/or had received previous substance abuse treatment. Affective disorder, suicide attempt, and antisocial personality were frequent in this group. About half of the patients complied with treatment and showed improvement in their substance disorder. Several common themes in the management of these patients are described.