The effects of alcohol abuse on HIV disease progression have not been definitively established. A prospective, 30-month, longitudinal study of 231 HIV(+) adults included history of alcohol and illicit drug use, adherence to antiretroviral therapy (ART), CD4(+) cell count, and HIV viral load every 6 months. Frequent alcohol users (two or more drinks daily) were 2.91 times (95% CI: 1.23-6.85, p = 0.015) more likely to present a decline of CD4 to <or=200 cells/microl, independent of baseline CD4(+) cell count and HIV viral load, antiretroviral use over time, time since HIV diagnosis, age, and gender. Frequent alcohol users who were not on ART also increased their risk for CD4 cell decline to <or=200 cells/mm(3) (HR = 7.76: 95% CI: 1.2-49.2, p = 0.03). Combined frequent alcohol use with crack-cocaine showed a significant risk of CD4(+) cell decline (HR = 3.57: 95% CI: 1.24-10.31, p = 0.018). Frequent alcohol intake was associated with higher viral load over time (beta = 0.259, p = 0.038). This significance was maintained in those receiving ART (beta = 0.384, p = 0.0457), but not in those without ART. Frequent alcohol intake and the combination of frequent alcohol and crack-cocaine accelerate HIV disease progression. The effect of alcohol on CD4(+) cell decline appears to be independent of ART, through a direct action on CD4 cells, although alcohol and substance abuse may lead to unmeasured behaviors that promote HIV disease progression. The effect of alcohol abuse on viral load, however, appears to be through reduced adherence to ART.