Clinical trials have shown that the prophylactic use of zidovudine and aerosolized pentamidine (or other antibiotics used as prophylaxis against Pneumocystis carinii pneumonia) in acquired immunodeficiency syndrome (AIDS)-free human immunodeficiency virus (HIV)-infected persons delays the development of AIDS, but the effectiveness of such therapy in general use in the population still remains largely undocumented. To help answer this question, the authors estimate the effectiveness of this therapy in a population-based cohort of HIV-infected homosexual and bisexual men in San Francisco. The authors use a continuous-time Markov process to model the decline of CD4+ T-lymphocytes (T4-cells) measured in cells/microliter in HIV-infected persons. The model partitions the HIV (type 1) infection period into six progressive T4-cell count intervals (stages), followed by a seventh stage: AIDS diagnosis. The authors use maximum likelihood methods to fit the model to the observed transitions for 428 HIV-infected men during June 1984 to March 1991, from the San Francisco Men's Health Study. Since zidovudine was not widely used before 1988, the model has a component that controls for calendar time-related biases. The fitted model provides statistical estimates and confidence intervals for measuring therapy effectiveness. The authors estimate that prophylactic therapy reduces the progression rate from stage 4 (T4-cell count, 350-499) to stage 5 (T4-cell count, 200-349) by a factor of 0.26 (95% confidence interval (CI) -0.22 to 0.55); from stage 5 to stage 6 (T4-cell count < 200) by a factor of 0.33 (95% CI 0.04-0.54); and from stage 6 to 7 (AIDS) by a factor of 0.62 (95% CI 0.47-0.73). In addition, therapy started by an HIV-infected person in stage 4 is estimated to reduce the risk of developing AIDS by a factor of 0.83 (95% CI 0.46-0.94) at 6 months and 0.68 (95% CI 0.35-0.89) at 24 months after entering stage 4. Therapy started by HIV-infected persons in more advanced stages is estimated to reduce the risk of developing AIDS by factors ranging from 0.70 (95% CI 0.39-0.90), early in stage 5, to 0.28 (95% CI 0.14-0.45), late in stage 6. Thus, the prophylactic use of zidovudine and pentamidine in routine medical care has a strong, consistent, and significant effect in slowing the clinical course of HIV infection in a population-based cohort.