Rotavirus illness has been linked to childhood seizures. We investigated whether a protective association exists between receipt of rotavirus vaccine and being hospitalized or visiting the emergency department for seizures in the year after vaccination. We retrospectively analyzed a cohort of children born after 28 February 2006 (when rotavirus vaccine was licensed in the United States) and enrolled in the Vaccine Safety Datalink (VSD) through November 2009. Seizure rates from 4 to 55 weeks following last rotavirus vaccination were compared by vaccine exposure status (fully vaccinated and unvaccinated). A time-to-event analysis using a Cox proportional hazards model was performed, accounting for time-varying covariates. We calculated the relative incidence of seizure compared by vaccine exposure status during the postexposure interval. Our cohort contained VSD data on 250 601 infants, including 186 502 children fully vaccinated (74.4%) and 64 099 (25.6%) not vaccinated with rotavirus vaccine. Rates of seizures were associated with rotavirus vaccination status. After adjusting for covariates (VSD site, age at last dose, sex, and calendar month of the index date), a statistically significant protective association was observed between a full course of rotavirus vaccination vs no vaccination for both first-ever seizures (risk ratio [RR] = 0.82; 95% confidence interval [CI], .73-.91) and all seizures (RR = 0.79; 95% CI, .71-.88). A full course of rotavirus vaccination was statistically associated with an 18%-21% reduction in risk of seizure requiring hospitalization or emergency department care in the year following vaccination, compared with unvaccinated children. This reduction in childhood seizures complements the well-documented vaccine-related benefit of preventing US diarrhea hospitalizations.