OBJECTIVE: To determine predictors of mortality and changes in those predictors over time on combination antiretroviral therapy (cART) in South Africa. DESIGN: A cohort study. METHODS: Using routine clinic data with up to 4 years follow-up after antiretroviral therapy initiation and with death ascertainment from a national vital statistics register, we used proportional hazards modeling to assess baseline and time-updated predictors of mortality and changes in strength of those predictors over time on cART. Furthermore, we compared CD4 count among individuals who died by duration on cART. RESULTS: Fifteen thousand sixty subjects (64% men, median CD4 count 127 cells/mm³) started antiretroviral therapy between January 2003 and January 2008. Over a median follow-up of 1.8 years, 2658 subjects died. The baseline characteristics of WHO stage, hemoglobin, CD4 count, HIV RNA level, and symptoms were all associated with mortality during the first 12 months of cART but lost association thereafter. However, time-updated factors of CD4 count, body mass index, symptoms, anemia, and HIV RNA suppression remained strong predictors of death. Most recent CD4 count before death rose from 71 during the first 3 months of cART to 175 cells per cubic millimeter after >3 years of cART. CONCLUSION: Over 4 years of cART, risk of death declined and associations with mortality changed. An increase in CD4 count at death and changing associations with mortality may suggest a shift in causes of death, possibly from opportunistic infections to other infections and chronic illnesses.