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Rotaviruses (RVs) are the leading cause of acute gastroenteritis in children, while histo-blood group antigens (HBGAs) are believed to be host attachment and susceptibility factors of RVs. A large case–control study nested in a population-based diarrhea surveillance targeting children <5 y of age was performed in rural Hebei province, north China. Saliva and serum samples were collected from all participants to determine HBGA phenotyping, FUT2 mutations, and RV IgG antibody titers. A logistic model was employed to assess the association between host HBGA secretor status and risk of RV infection. Among 235 RV cases and 680 non-diarrhea controls studied, 82.4% of participants were IgG positive by an average age of 77 months. Out of the 235 RV cases, 216 (91.9%) were secretors, whereas the secretor rate was 76.3% in the non-diarrhea controls, resulted in an adjusted OR of 3.0 (95%CI: 1.9–4.7, P < .0001) between the two groups. Our population-based case–control study indicated a strong association between host HBGA secretor status and risk of RV infection in Chinese children. The high prevalence of Lewis-positive secretor status strongly suggests that Chinese children may be genetically susceptible to current co-circulating RV strains, and thus, a universal childhood immunization program against RV disease should be successful in China.