The major histocompatibility complex (MHC) class II B locus of the striped bass (Morone saxatilis) was found to contain multiple forms of the class II B gene. Seven complete MHC class II B cDNA clones were isolated and sequenced, identifying five unique allelic forms of a MHC class II B gene. Among three specimens, each representing a geographically distinct population (Chesapeake Bay, MD; Roanoke River, NC; and Santee-Cooper Reservoir, SC) extensive variability was detected in the beta(1) encoding domain, which corresponds with the functional peptide-binding region (PBR) of known MHC class II molecules. The location of variable amino acid residues in the beta(1) domains corresponds with polymorphic sites observed in other teleosts and higher vertebrates. The amino acid translated beta(2) domain encoding regions, transmembrane regions, and cytoplasmic regions of the five clones correlated well with those of known vertebrate MHC class II proteins. Seventy-one percent of the variability found within the presumed PBR encoded at the MHCMosa class II B locus corresponded with that of the PBR of a human MHC class II B gene. Overall, the Mesa sequences showed greatest similarity to the MHC class II B genes of cichlid fishes, as expected from phylogenetic relationships.