Technical Abstract: Weight loss is an independent risk factor for mortality in HIV, but the role of drug use in HIV-related weight loss is not well described. We conducted this study to determine the role of drug abuse in HIV-related weight loss. Men (n=304), all of whom were Hispanic, were recruited into one of three groups: HIV-infected drug users, HIV-non-infected drug users, and HIV-infected non-drug users. Body mass index (BMI) was measured at successive visits. The groups were re-categorized based on self-reported drug use at the current visit into: 1) users of cocaine alone 2) users of cocaine and opiates 3) users of opiates alone 4) former drug users and 5) those who denied ever using drugs (all HIV-infected). The effect on BMI of the duration of use of the specific drug types was evaluated using repeated-measures analyses. Longer duration of exclusive opiate use or mixed cocaine and opiate use did not affect BMI in the men, regardless of HIV status. Exclusive cocaine use was associated with a decline in BMI among HIV-infected men (-0.070 kg/m2 per month duration of use, SE=0.033, P=0.037), but not among HIV-uninfected men (0.024 kg/m2 per month, SE=0.023, P=0.29). Adjustment for marijuana, cigarette and alcohol use in all men, or for CD4 count, viral load, or HIV medication use in the HIV-infected men did not alter the conclusions. We conclude that the use of opiates or combined opiates and cocaine does not increase the risk of weight loss in the presence or absence of HIV infection. Exclusive cocaine use may exacerbate weight loss in HIV-infection.