BACKGROUND: During the first year that the rhesus rotavirus tetravalent vaccine (RRV-TV) was licensed, the Vaccine Adverse Event Reporting System received several reports of intussusception after vaccination. To evaluate the risk of intussusception, we conducted a retrospective cohort study in ten managed care organizations. METHODS: Cases of intussusception were identified by searching electronic databases for diagnoses of intussusception (ICD-9 Code 560.0) in infants 1 to 11 months of age and confirmed by medical chart review. Vaccination and enrollment data were obtained from administrative databases. Incidence rate ratios (RR) of intussusception were computed by dividing incidence rates in prespecified risk intervals after vaccination by the background rate of intussusception and adjusted for age by Poisson regression. Cox proportional hazard regression was used to evaluate risk by vaccine dose. RESULTS: Of 463,277 children 56,253 had been vaccinated with a total of 91 371 doses of RRV-TV. The incidence rate of intussusception was 25/100,000 person years among unexposed infants and 340/100,000 person years 3 to 7 days postvaccination. In the interval 3 to 7 days after vaccination, the age-adjusted RR was 16.0 (95% confidence interval, 5.5 to 46.7) for all doses combined and 30.4 (95% confidence interval, 8.8 to 104.9) after the first dose. RRs for the 8- to 14- and 15- to 21-day risk intervals were >1.0, but the confidence intervals substantially overlapped 1.0. The attributable risk was one case of intussusception per 11 073 children vaccinated. CONCLUSIONS: RRV-TV is associated with an increased risk of intussusception. The risk is greatest 3 to 7 days after the first vaccination dose.