This study evaluates the association of cocaine use with short-term change in CD4 counts among human immunodeficiency virus type 1 (HIV-1) seropositive, minority injecting drug users prior to the introduction of zidovudine (AZT). Ninety-eight HIV-1 seropositive subjects were recruited from six inner-city, methadone maintenance clinics. A baseline assessment included a short questionnaire regarding drug behavior and quantitation of CD4 cell counts. These measures were repeated on all subjects 3 to 4 months later. Thirty-eight subjects reported using cocaine between baseline and 4-month follow-up evaluations. Males and African Americans were more likely to be cocaine users (P < .01). Cocaine users were more likely to engage in heroin and needle use (P < .001). Cocaine users experienced a significant decline in CD4 cells compared with nonusers (P = .013); no marked difference in CD4 decline was noted between heroin users and nonusers (P = .19). Multivariate analysis showed that a decline in CD4 counts was 2.82 times more likely to occur in cocaine users than in cocaine nonusers (90% two-sided confidence interval of 1.08, 7.37). These findings support the hypothesis of a possible link between cocaine use and short-term CD4 decline in HIV-1 seropositive injecting drug users.