Continuous evaluation of child survival is needed in sub-Saharan Africa where HIV prevalence among women of reproductive age continues to be high. We examined mortality levels and trends over a period of ∼20 years among HIV-unexposed and -exposed children in Blantyre, Malawi. Data from 5 prospective cohort studies conducted at a single research site from 1989 to 2009 were analyzed. In these studies, children born to HIV-infected and -uninfected mothers were enrolled at birth and followed longitudinally for at least 2 years. Information on sociodemographic, HIV infection status, survival, and associated risk factors was collected in all studies. Mortality rates were estimated using birth-cohort analyses stratified by maternal and infant HIV status. Multivariate Cox regression models were used to determine risk factors associated with mortality. The analysis included 8286 children. From 1989 to 1995, overall mortality rates (per 100 person-years) in these clinic-based cohorts remained comparable among HIV-uninfected children born to HIV-uninfected mothers (range 3.3-6.9) or to HIV-infected mothers (range 2.5-7.5). From 1989 to 2009, overall mortality remained high among all children born to HIV-infected mothers (range 6.3-19.3) and among children who themselves became infected (range 15.6-57.4, 1994-2009). Only lower birth weight was consistently and significantly (P < 0.05) associated with higher child mortality. HIV infection among mothers and children contributed to high levels of child mortality in the African setting in the pretreatment era. In addition to services that prevent mother-to-child transmission of HIV, other programs are needed to improve child survival by lowering HIV-unrelated mortality through innovative interventions that strengthen health infrastructure.