A cohort of 544 human immunodeficiency virus-1 (HIV-1) seropositive intravenous drug users (IVDUs) was recruited in 1988 and early 1989; data on laboratory markers, clinical symptoms, intravenous drug use, and demographics were collected. Forty-one IVDUs developed AIDS within 2 years of enrollment. Data were analyzed using methods of survival analysis. None of the individuals reported use of antiviral agents or Pneumocystis carinii prophylaxis at baseline. A very strong (p less than 0.001) dose-response relationship was identified between CD4 cell count at baseline and the subsequent development of AIDS. In multivariate analysis, both the presence of more than one clinical HIV-1-related symptom and serum neopterin greater than 12 nmol/L showed significant associations with the relative hazard (95% confidence interval) of AIDS after controlling for CD4 of 2.9 (1.6, 5.6) and 2.0 (1.0, 3.7), respectively. In these IVDUs, serum beta 2-microglobulin did not add predictive power for progression to AIDS. The effect of clinical symptoms was stronger for high CD4 cell counts, indicating the need to monitor HIV seropositive IVDUs with both laboratory studies and clinical evaluation.