BACKGROUND: We compared morbidities in HIV-1-infected patients before and after the introduction of antiretroviral therapy (ART) in a rural Ugandan cohort followed from 1990 to 2008. ART was introduced in 2004. METHODS: Random-effects Poisson regression models were used to estimate incidence rates of World Health Organization (WHO) stage-defining diseases in HIV-infected individuals aged 13 years or older with known seroconversion dates, and in an age-stratified sample of HIV-negative individuals. RESULTS: The most common morbid event was bacterial pneumonia, with an incidence of 7.4/100 person-years (pyr) among 309 HIV seroconverters and 1.3/100 pyr among 348 HIV-negative participants [hazard ratio (HR) 5.64; 95% confidence interval (CI) 3.6-8.8]. Among seroconverters, the incidence of the acquisition of any WHO stage-defining disease rose from 14.4/100 pyr (95% CI 11.1-18.6) in 1990-1998 to 46.0/100 pyr (95% CI 37.7-56.0) in 1999-2003. Following the introduction of ART, the incidence among seroconverters declined to 36.4/100 pyr (95% CI 27.1-48.9) in 2004-2005 and to 28.3/100 pyr (95% CI 21.2-37.8) in 2006-2008. At the individual level, a higher rate of acquiring any WHO stage-defining disease was independently associated with lower CD4 cell count, longer duration of HIV infection and older age. In addition, individuals who had been on ART for longer than 12 months had a substantially lower rate of any WHO stage disease than those not yet on ART (adjusted HR 0.35; 95% CI 0.2-0.6). CONCLUSION: Morbidity in HIV-positive participants decreased following the introduction of ART, and this decline was more marked with increasing duration on ART. The benefits of decreased HIV-related morbidity from ART lend support to urgent efforts to ensure universal access to early diagnosis of HIV infection and to ART, especially in rural Africa.