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Background Norovirus is a leading cause of acute gastroenteritis worldwide. Improved diagnostic capability has been instrumental in the characterization of archival norovirus strains associated with gastroenteritis outbreaks that were investigated decades ago. One such investigation was that of 2 sequential gastroenteritis outbreaks that occurred in 1971 at the former Henryton State Hospital in Maryland. Approximately 40% of the resident population experienced clinical symptoms in both outbreaks, which occurred 11 months apart. Methods Stored stools and paired sera were re-analyzed to investigate the etiology of the 2 outbreaks. Results Different norovirus genotypes were identified as the etiological agents responsible for the illnesses, with GII.2 associated with the first outbreak and GII.6 with the second. The viruses were antigenically distinct as determined by analyses of hyperimmune sera raised against the corresponding virus-like particles in animals, as well as paired sera from infected individuals. Conclusions The observed antigenic differences were consistent with the failure of the GII.2 strain to provide cross-protective immunity to the GII.6 strain a few months later. An understanding of antigenic diversity among norovirus genotypes will be important in the design of norovirus vaccines.