African American (AA) women comprise only 12% of US females, and yet account for 66% of new HIV infections in women. The rate of AIDS diagnosis for black women (45.5/100,000 women) is approximately 23 times the rate for white women. In fact, HIV/AIDS-related conditions are now the leading cause of death from AA women aged 25-34. Heavy/hazardous alcohol use impacts HIV/AIDS disease progression and treatment, particularly in women. HIV-infected, hazardous drinking women are less likely to be prescribed antiretroviral therapy and to achieve effective viral load reductions, and they have increased mortality compared to nonhazardous drinking, HIV-infected women and even hazardous drinking, HIV-infected men. Clearly this population is an important target for effective alcohol treatments. The proposed placebo controlled, randomized clinical trial will investigate the efficacy of ondansetron pharmacotherapy for the treatment of hazardous alcohol use and alcohol abuse/dependence among HIV-infected, AA women. Ondansetron, a 5-HT3 antagonist, has been selected because of evidence of effectiveness in persons who want to reduce their drinking but are not abstinent at the start of medication; evidence of moderate to strong effects in early onset drinkers, a characteristic that is overrepresented in our clinic patients; and a mild side-effects profile, making it an ideal drug for patients who are often receiving multiple other medications with significant side-effects. HIV-infected, hazardous drinking, AA women will be randomized to placebo, low dose (0.2 mg bid) and moderate dose (0.8 mg bid) ondansetron. Subjects will be classified by age-of-onset for alcohol problems and genotyped for a functional polymorphism of the serotonin transporter gene. Outcomes will include alcohol use and related symptoms, medication safety and side-effects, HIV biomarkers and treatment compliance, HIV risk behaviors, and quality of life. This study will provide important new scientific and clinical information on ondansetron for alcohol pharmacotherapy in HIV-infected, African American women. PUBLIC HEALTH RELEVANCE: African American women comprise only 12% of US females, and yet account for 66% of new HIV infections in women. Hazardous alcohol use negatively affects HIV/AIDS disease progression and treatment, particularly in women. The proposed randomized clinical trial will investigate a novel pharmacotherapy for hazardous drinking, HIV infected, African American women, using the 5-HT3 antagonist ondansetron. This study will provide important new safety and efficacy results on drinking and HIV outcomes.