We conducted a study to identify predictors of the wasting syndrome among human immunodeficiency virus 1 (HIV-1)-seropositive injecting drug users. We enrolled 113 cases (defined as an unexplained loss of > 10% baseline weight) and 226 controls (defined as < 5% weight loss or any weight gain) from a HIV-1-seropositive cohort of injecting drug users (N = 630) into a nested case-control study. Crude predictors of wasting included: older age [odds ratio (OR) for a 1-year difference = 1.06], female gender (OR = 1.66), more years spent injecting drugs (OR for 1-year difference = 1.05), presence of diarrhea (OR = 3.78), lower percentage of CD4 T-lymphocytes (OR for 10-unit difference = 0.73), and higher log beta 2-microglobulin concentration (OR for 1 log difference = 11.3). After adjusting for CD4 cell level, beta 2-microglobulin concentration, diarrhea, gender, length and frequency of drug use, age, the presence of thrush, and education, independent predictors of weight loss in HIV-seropositive injecting drug users were female gender (OR = 2.23) and increasing age (OR for 1-year difference = 1.06). Frequency and duration of drug use were not strongly associated with the odds of developing wasting syndrome in this HIV-1-seropositive cohort. These data indicate that HIV wasting syndrome in injecting drug users is distinct from complications of drug use.