B lymphocytes from DBA/2Ha mice have a genetic defect characterized by a failure to differentiate into antibody-secreting cells in response to a family of lymphokines termed B cell maturation factors (BMFs). By contrast, B cells from DBA/2Ha mice respond normally in PFC assays to the B cell mitogen LPS, and macrophages from these mice are activated by one of the three BMFs. Two loci are responsible for the B cell defect in DBA/2Ha mice. One locus (Bmfr-1) is constitutively expressed throughout life, and maps approximately 13 cM distal to the brown locus on chromosome 4. A second locus (Bmfr-2) becomes active only after sexual maturity and is closely linked to the dilute locus on chromosome 9. At both loci, alleles determining responsiveness to BMFs are dominant over nonresponder alleles. The effect of Bmfr-2 on B cell responsiveness may be related to levels of the steroid sex hormones. DBA/2Ha mice offer a tool for studying the genetic and hormonal regulation of the immune system.