Background : Rotavirus is considered to be the most common cause of serious acute dehydrating diarrhea worldwide. However, there is a scarcity of information on rotavirus disease burden in sub-Saharan Africa. Methods : We conducted prospective, hospital-based surveillance for rotavirus diarrhea among children 5 years of age at the tertiary care Dr. George Mukhari Hospital (DGM) and at the Brits district Hospital (BH) in the Gauteng and North West Provinces in South Africa; we estimated that up to 80% of children under 5 years of age in their catchment areas who are hospitalized for diarrhea are admitted to one of these hospitals. Results: At DGM, 2553 children under 5 years of age were admitted for diarrhea from January 2003 through December 2005, and 852 children under 5 years of age were treated for diarrhea at BH during 2004–2005. We examined stool specimens from 450 children (53%) at BH and from 1870 children (73%) admitted to DGM. An estimated 22.8% (95% confidence interval [CI], 21.2%–24.5%) of the children hospitalized with diarrhea at DGM were rotavirus positive, and the corresponding figure at BH was 18.2% (95% CI, 14.9%–22.1%). Among children under 5 years of age admitted to DGM for any reason, an estimated 5.5% (95% CI, 5.1%–6.0%) had rotavirus diarrhea. Our incidence estimates suggest that 1 in 43–62 children in the area is likely to be hospitalized with rotavirus. diarrhea by 2 years of age. Conclusions: Prevention of serious rotavirus illness by vaccination will substantially reduce not only the disease. burden among young children but also the case load in South African health care facilities. ; Present affiliations : Life and Consumer Sciences, University of South Africa (Florida Campus), Johannesburg, South Africa (J.B.D.); Gastroenteritis and Respiratory Viruses Laboratory Branch, Division of Viral Diseases, National Center for Immunizations and Respiratory Disease, Centers for Disease Control and Prevention, Atlanta, Georgia (M.D.E.); and Vaccines and Immunization, PATH, Seattle, Washington (A.D.S.). ; Financial support: World Health Organization (V27/181/159), the Norwegian Programme for Development, Research and Higher Education (PRO 48/2002), the South African Medical Research Council, and the Poliomyelitis Research Foundation (PRF 04/06). Potential conflicts of interest: none reported. Supplement sponsorship: This article is part of a supplement entitled “Rotavirus Infection in Africa: Epidemiology, Burden of Disease, and Strain Diversity,” which was prepared as a project of the Rotavirus Vaccine Program, a partnership among PATH, the World Health Organization, and the US Centers for Disease Control and Prevention, and was funded in full or in part by the GAVI Alliance.