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In the German federal state Mecklenburg-Western Pomerania, routine rotavirus (RV) vaccination in infants has been recommended since 2009. The effectiveness of RV vaccination was investigated after an unexpectedly high number of RV infections in fully vaccinated children occurred.Intensified RV surveillance was performed in Mecklenburg-Western Pomerania between 2010 and 2011. The screening method was applied to assess vaccine effectiveness (VE) in children up to 24 months after vaccination. To identify risk factors for breakthrough infections, a case-control study and genotyping were conducted in vaccinated and unvaccinated RV-infected children.VE for the prevention of RV infection requiring medical attention or hospitalization was 68% (95% confidence interval [CI]: 61–71) and 80% (95% CI: 77–83), respectively. VE for preventing hospitalization but not medical attention remained stable over 2 years. Vaccinated were less often hospitalized (23%) than unvaccinated RV-infected children (61%; P < 0.001). Breastfeeding (odds ratio, 3.99; 95% CI: 1.92–8.27) and attending daycare (odds ratio, 3.42; 95% CI: 1.64–7.12) were independently associated with breakthrough infections. Genotype G1P was detected more frequently in RotaTeq-vaccinated (44% versus 11%; P < 0.03) and G2P in Rotarix-vaccinated children (42% versus 6%; P < 0.02).RV vaccination protects young children effectively from RV disease and can reduce disease severity. Breastfeeding might impair VE, but further research is needed to identify the critical time window for this interference and to develop appropriate recommendations.