Despite widespread nutrient deficiencies, a substantial proportion of the MIDAS cohort exhibits obesity, which has been linked to immune dysregulation in other clinical settings. Herein, the effects of obesity on immune function, disease progression, and mortality were evaluated longitudinally in 125 HIV-1-seropositive drug users, with comparison measures in 148 HIV-1-seronegative controls. Data were collected at a community clinic from 1992 to 1996, before administration of highly active antiretroviral therapy. Results indicated that overweight/obesity, defined as body mass index (BMI; kg/m2) > or =27, was evident in 18% of the HIV-1-seropositive patients and 29% of the seronegative patients. At baseline, no significant immunologic differences were observed among lean, nonobese, and obese groups. Over an 18-month period, 60.5% of the nonobese HIV-1-seropositive patients exhibited a 25% decline in CD4 cell count, compared with 18% of the obese patients (p<.004). During the follow-up period, 38% of the lean and 13% of the nonobese study subjects died of HIV-1-related causes. Measurements of BMI were inversely associated with progression to death, independent of CD4 count <200 cells/mm3 (p<.02). These data suggest that mild-to-moderate obesity in HIV-1-infected chronic drug users does not impair immune function and is associated with better HIV-1-related survival.