Background: A comprehensive evaluation of associations between the susceptibility to norovirus infections and histo-blood group antigens is not available in the Taiwanese population, in which the nonsecretor phenotype is absent. Methods: A 1: 1 matched case-control study was conducted in northern Taiwan from February 2013 to December 2014 when an epidemic of norovirus infection occurred. Cases were children <18 years old who were hospitalized because of diarrhea and were found to have laboratory-confirmed norovirus infections. Controls were healthy children matched to the cases by age and gender. The norovirus genotype was determined by polymerase chain reaction sequencing of the VP1 gene. The secretor status, Lewis antigen and ABO type were determined by characterization of genetic polymorphisms in the FUT2, FUT3 and ABO genes, respectively. Results: A total of 147 case-control pairs were included. GII. 4 Sydney strain was the major genotype and identified in 78.3% of the cases. The weak-secretor and Lewis-positive genotypes were less commonly identified in cases than in controls (5.4% vs. 23.1% and 79.6% vs. 89.8%, respectively). Multivariate analysis revealed that the secretor and Lewis-negative genotypes were both independent factors associated with increased risk of norovirus infections [matched odds ratio: 6.766, 95% confidence interval (CI): 2.649-17.285, P0.05). Conclusion: The weak-secretor genotype and the Lewis antigen-positive genotype were both protective factors against severe norovirus gastroenteritis during the GII. 4 Sydney strain epidemic in Taiwan.