We isolated and determined the sequences of two human germ-line heavy chain variable region (V(H)) genes and compared them with mouse V(H) genes. The results show that the human V(H)I subgroup is evolutionarily related to the mouse V(H)II subgroup. Evolutionary preservation of homologies in V(H) genes of the same subgroup includes not only the coding region but also intron size and homology in noncoding regions. This suggests that a V(H) gene subgroup constitutes a multigene family that undergoes concerted evolution. The homology between genes of the same subgroup in different species is greater than that between genes of different subgroups within a species. One of the V(H)II genes contains, in complementarity-determining region 2 (CDR2), a 13-base-pair previously shown to be in CDR2 of a V(H)III gene and in a heavy chain diversity region gene, D(H), suggesting the insertion of diversity region gene sequences into the V(H) gene. One of the human V(H) genes is a pseudogene because of a terminator, which, together with our previous results, shows that the V(H) gene repertoire contains 40% pseudogenes. In one of the V(H) genes, direct and inverted repeats at both 5' and 3' ends of the gene suggest a potential transposable element that encompasses the entire V(H) gene. It is possible that such a structure may facilitate saltatory replication and rapid expansion of V(H) gene families.