We have investigated the extent of genetic variation and the number of germ-line heavy-chain-variable (VH) genes to obtain information on the organization and repertoire of the VH genes. Our studies revealed extensive genetic variation in this region, indicated by restriction-endonuclease site polymorphisms. Analysis of the distribution of selected polymorphic loci revealed evidence of linkage disequilibrium, particularly between VH2 and VH3 subclass loci, indicating that the subclasses are interdispersed in the human germ-line chromosome. Absolute correlation was detected between alleles of a VH2 locus and the alleles of three VH3 loci, evidence for an extra set of VH genes, which are present in 48% of the Caucasian population. A preliminary estimate of the number of VH genes, approximately 50, indicates a smaller number of VH genes than suggested by the amount of protein variation. The extensive genetic variation we have observed may be associated with genetic differences in the immune response and potentially with variable susceptibility to autoimmune disorders.