The N-terminal sequences from heavy variable regions of 47 myeloma proteins of the NZB mouse have been analyzed. Sixteen of these VH regions have unblocked alpha amino groups and have been analyzed over their N-terminal 20 residues by automatic sequence analysis. These sequence data along with the antigen-binding profiles and immunoglobulin class distribution are compared with comparable data from BALB/c myeloma proteins. These comparisons suggest that the NZB and BALB/c populations of myeloma proteins are distinct from one another. The genetic implications of this conclusion are discussed.