Background.Withdrawal of the tetravalent rhesus-human rotavirus vaccine Rotashield because of its association with intussusception raised concerns about a potential link between natural rotavirus disease and intussusception. Our objective was to determine whether such an association exists.Methods.In the Southern California Kaiser Permanente Health Care Plan, a large health maintenance organization, from October, 1992, to July, 1999, we retrospectively identified by computerized data and medical charts all children <3 years old with intussusception, and from 1997 to 1999 we independently identified by prospective clinical and laboratory evaluation children <3 years old with rotavirus diarrhea. We compared the epidemiologic characteristics of intussusception and rotavirus infection in our study population and evaluated for the presence of both diseases in individual patients.Results.Using computerized data we identified 124 cases of intussusception, 101 (81%) of which were confirmed by medical chart and radiologic reviews. The incidences for infants <1 year old and for children <3 years old were 41 (95% confidence interval, 32 to 55) and 17 (95% confidence interval, 13 to 20) per 100 000 child years, respectively. Between November 1997 and July 1999, we identified 470 cases of rotavirus diarrhea and none had intussusception. Although rotavirus diarrhea had a distinct peak incidence between December and February, intussusception had no apparent seasonality. The age distributions overlapped, but intussusception occurred at an earlier age than rotavirus disease.Conclusions.We found no epidemiologic evidence for an association between intussusception and natural rotavirus infection, but our study was limited by an insufficient number of cases to definitively exclude a causal link. The dramatic winter peak of rotavirus disease had no discernable parallel in the incidence of intussusception. Our data suggest that the association between tetravalent rhesus-human rotavirus vaccine and intussusception may possibly result from the nonhuman rotavirus components of that vaccine.