The response to highly active antiretroviral treatment (HAART) and predictors of mortality among patients with advanced HIV infection (CD4(+) cell count <50 cells/mm(3)) in Botswana are described. Clinical and laboratory data for 349 patients with CD4 <50 cells/mm(3) initiating HAART from January 23 to November 18, 2002 at Princess Marina Hospital in Gaborone, Botswana were extracted from clinical charts and electronic patient management systems. The Kaplan-Meier method was used to estimate survival and log-rank tests used for group comparisons. Cox regression was used to identify independent predictors of survival. A total of 349 adults initiated HAART. In all, 78.2% (95% CI: 73.7%, 82.9%) of patients survived 1 year. Among survivors, the mean CD4(+) cell count increase was 239.8 cells/mm(3) (95% CI: 217.0, 262.8) at 12 months; 92.1% (95% CI: 87.8%, 94.9%) of patients (as treated) had plasma HIV-1 RNA < or =400 copies/ml at 9 months declining to 59.9% (95% CI: 54.7%, 64.9%) (ITT). There was a 2-fold higher mortality rate among patients with CD4(+) < or =10 cells/mm(3) compared to 11-49 cells/mm(3), hazard ratio (HR) = 1.91 (95% CI:1.16, 3.14). A 10 cell/mm(3) higher CD4(+) cell count corresponded to a 22% decrease in hazard of death (HR = 0.78; 95% CI: 0.64, 0.94). Lower baseline CD4(+) cell count (p < 0.001) and WHO clinical stage 4 HR = 2.41 (95% CI:1.32, 4.38) were independent predictors of poorer survival. HAART confers significant benefit even among persons with advanced immunosuppression. Adults with CD4(+) cell counts < or =10 cells/mm(3) and/or WHO clinical stage 4 disease at the time of HAART initiation have a higher risk of death.