OBJECTIVES: To determine the impact of HIV on child mortality and explore potential risk factors for mortality among HIV-infected and HIV-exposed uninfected children in a longitudinal cohort in rural Uganda. METHODS: From July 2002 to March 2010, HIV-infected and HIV-exposed uninfected children aged 6 weeks-13 years were enrolled in an open population-based clinical cohort. Antiretroviral therapy (ART) was introduced in 2005. Clinical and laboratory data were collected every 3 months. Person-years at risk were calculated from time of enrolment until earliest date of ART initiation, death or last visit. Cox regression was used to estimate hazard ratios (HR) for mortality. RESULTS: Eighty-nine (30.2%) HIV-infected and 206 (69.8%) HIV-exposed but uninfected children were enrolled. Twenty-one children died. The mortality rate was six times higher in ART-naive HIV-infected children than in HIV-exposed but uninfected children (HR = 6.4, 95% CI = 2.4-16.6). Among HIV-infected children, mortality was highest in those aged <2 years. Decreasing weight-for-age Z (WAZ) score was the strongest risk factor for mortality among HIV-infected children (HR for unit decrease in WAZ = 2.6, 95% CI = 1.6-4.1). Thirty-five children (aged 7 months-15.6 years; median, 5.4 years) started ART. CONCLUSIONS: Mortality among HIV-infected children was highest among those aged <2 years. Intensified efforts to prevent mother-to-child transmission of HIV and ensure early HIV diagnosis and treatment are required to decrease child mortality caused by HIV in rural Africa.