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 <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 <5 years of age were admitted for diarrhea from January 2003 through December 2005, and 852 children <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 <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.