Host immune responses to human caliciviruses are difficult to study because of the lack of a clear definition of antigenic or serological types. This report describes antibody responses to several Norwalk-like viruses in large outbreaks of acute gastroenteritis on 2 US Navy ships. Enzyme immunoassays (EIAs) were used to measure antibody responses. To understand the antibody response to a homologous strain causing the outbreaks, the viral capsid gene of one isolate (C59) was expressed in baculovirus and included in the EIAs. Significantly greater seroresponses were detected in patients against the homologous strain than against the heterologous strains. Strains within genogroups reacted more strongly than did strains between genogroups. Significantly higher antibody titers against the outbreak strain were detected in acute serum samples from control subjects than in those from case patients. These results indicate that recombinant EIAs are useful for outbreak investigation and that the homologous antibody might be protective against reinfection.