AbstractBackground: The etiology of intussusception (IS), a serious medical condition of acute gastrointestinal obstruction, remains unclear. Limited evidence suggests a role for viral infections, including rotavirus infection. This study aimed to explore the risk of IS after rotavirus gastroenteritis (RV GE) in the first year of life, where the incidence of IS is highest. Methods: In this retrospective, self-controlled case series (SCCS), we assessed the risk of IS after RV GE in infants <1 year of age, using data extracted from administrative claims databases in the United States. Incidence rate ratios (IRR) of IS were calculated for the 7- and 21-day risk periods after RV GE (main analysis) or after fracture (sensitivity analysis using a control event) in subjects presenting with claims for these conditions. Post-hoc analyses were also performed. Results: Out of the 290,912,068 subjects screened, 42 subjects presented claims for RV GE and IS (RV GE group) and 66 presented claims for fracture and IS (fracture group). The IRR of IS after RV GE was 79.6 (95% confidence interval, CI: 38.6–164.4) in the 7-day risk period and 25.5 (95% CI: 13.2–49.2) in the 21-day risk period. The sensitivity analysis also showed an association between IS and fracture for the two risk periods: IRR was 6.1 (95% CI: 3.0–12.7) and 2.8 (95% CI: 1.5–5.4) in the 7- and 21-day risk periods, respectively, which suggested potential confounding such as by history of rotavirus vaccination, or a visit effect. Post-hoc analyses investigating these points did not confirm an association between fracture and IS, but still suggested a possible association between RV GE and IS. Conclusions: A temporal association between RV GE and IS was detected using the SCCS design in United States claims databases. However, due to some limitations identified through additional analyses, further studies are needed to confirm this association.