Changes in the level of CD4-bearing T-lymphocytes in injection drug users infected with the human immunodeficiency virus were evaluated in a sample of 318 subjects enrolled from a methadone program in the Bronx, New York, from 1985 through 1989. Follow-up continued through 1990. The percentage of CD4+ T-lymphocytes (CD4%) was used to maximize the stability of measurements. The rate of decline of the CD4% was determined using a random-effects assumption, and predictors of rate of decline were evaluated using an autoregressive model. The rate of CD4% decline was approximately 1.2 CD4% lost per 6 months, with a higher rate in recent seroconverters (2.2 CD4% lost). The most important predictors of decline of the CD4% in autoregressive models were current pyogenic bacterial infection (CD4% reduced by 2.75, 95% confidence interval (CI) 0.42-5.08), current report of a second constitutional symptom (CD4% reduced by 2.16, 95% CI 0.03-4.29), and history of bacterial infection (CD4% reduced by 1.49, 95% CI 0.09-2.89; proportion of prior CD4% lost increased by 0.14, 95% CI 0.01-0.27). Oral thrush was not related to an accelerated rate of CD4% decline.