Noroviruses are diverse positive-strand RNA viruses associated with acute gastroenteritis. Cross-reactive epitopes have been mapped primarily to conserved sequences in the capsid VP1 Shell (S) domain, and strain-specific epitopes to the highly variable Protruding (P) domain. In this work, we investigated a strain-specific linear epitope defined by MAb NV10 that was raised against prototype (Genogroup I.1) strain Norwalk virus (NV). Using peptide scanning and mutagenesis, the epitope was mapped to amino acids 21-32 (LVPEVNASDPLA) of the NV S domain, and its specificity was verified by epitope transfer and reactivity with a recombinant MAb NV10 single-chain variable fragment (scFv). Comparative structural modeling of the NV10 strain-specific and the broadly cross-reactive TV20 epitopes identified two internal non-overlapping sites in the NV shell, corresponding to variable and conserved amino acid sequences among strains, respectively. The S domain, like the P domain, contains strain-specific epitopes that contribute to the antigenic diversity among the noroviruses.