To determine whether DNA polymerase η plays a role in the hypermutation of immunoglobulin variable genes, we examined the frequency and pattern of substitutions in variable V H 6 genes from the peripheral blood lymphocytes of three patients with xeroderma pigmentosum variant disease, whose polymerase η had genetic defects. The frequency of mutation was normal but the types of base changes were different: there was a decrease in mutations at A and T and a concomitant rise in mutations at G and C. We propose that more than one polymerase contributes to hypermutation and that if one is absent, others compensate. The data indicate that polymerase η is involved in generating errors that occur predominantly at A and T and that another polymerase (s) may preferentially generate errors opposite G and C.