Highly active antiretroviral therapy (HAART) has decreased the morbidity and mortality of opportunistic infections including Pneumocystis jiroveci pneumonia (PCP) among HIV-infected individuals. We performed a hospital-based retrospective cohort study among a population of medically underserved inner city persons living in Atlanta, Georgia, diagnosed with confirmed PCP to compare the epidemiology and outcomes of PCP during 2 defined periods: 1990 to 1995, or pre-HAART period, and 1996 to 2001, or HAART period. A total of 488 patients were available for analysis. The overall mortality rate was 47% during the pre-HAART era compared with 37% during the HAART era (P = 0.02). However, among those patients that required medical intensive care unit admission and mechanical ventilation, the mortality rate was particularly high, with over 80% of patients dying as a result of their episode of PCP during both periods. PCP was the initial presentation of HIV infection in 39.3% in the pre-HAART period with a mortality rate of 52%, in contrast with 37% in the HAART period, with a mortality rate of 45%, respectively (P = NS). Only 30.7% in the pre-HAART period and 31.1% of patients in the HAART period were receiving PCP prophylaxis. The overall risk of death, when we combined both groups in the analysis, was higher for those patients who did not take PCP prophylaxis, those who smoked tobacco, and those who were admitted to the medical intensive care unit and required mechanical ventilatory support. Our findings suggest that despite the availability of HAART, PCP continues to cause a significant burden of disease among inner-city HIV-infected populations.