The immunoglobulin VH gene 51p1, a member of the large VH1 gene family, is preferentially expressed by B cells in the fetus and in chronic lymphocytic leukemia (CLL) and appears to be the source for many cryoglobulin rheumatoid factors. Polymorphism of 51p1 may therefore be functionally important. We have studied the germline representation of 51p1 and closely related VH elements to establish their prevalence and allelic relationship. A panel of oligonucleotide probes directed to the complementarity determining regions (CDR1 and CDR2) of 51p1 and a similar gene, hv1263, was used in restriction fragment polymorphism analysis of 48 unrelated individuals and six families. 13 VH alleles to the 51p1 locus were identified, each distinguished by its restriction fragment size, hybridization profile, or both. On some haplotypes the locus was duplicated. Null alleles were not seen. The 13 alleles were cloned, yielding nine distinct nucleotide sequences that were > 98.2% identical and included 51p1 and hv1263. These germline variations could influence specificity for antigen, because the corresponding protein sequences differed by up to five amino acids, including three nonconservative changes in the CDR. Two of the most prevalent variants contained 51p1. These findings expand the spectrum of polymorphism seen among human VH genes and elucidate the germline origin of VH1 sequences frequently expressed in autoantibodies and CLL. We conclude that the 51p1 locus is polymorphic, and that the 51p1 element is the predominant member of a complex set of alleles.