Some people are resistant to Norwalk virus (NV) infection; however, the factor(s) responsible for resistance or susceptibility to NV infection has not been identified. This study investigated the relationship between a person's ABO histo-blood group type and the risk of NV infection and symptomatic disease after clinical challenge. ABO phenotypes were identified by using serum samples from volunteers who participated in an NV challenge study (n=51). Individuals with an O phenotype were more likely to be infected with NV (odds ratio [OR], 11.8; 95% confidence interval [CI], 1.3-103), whereas persons with a B histo-blood group antigen had decreased risk of infection (OR, 0.096; 95% CI, 0.16-0.56) and symptomatic disease (OR, 0; 95% CI, 0-0.999). This is the first report demonstrating an association between a genetic factor and the risk of NV infection and symptomatic disease.