Both in vivo and in vitro, mice homozygous for the viable motheaten mutation show severe immunodeficiency, polyclonal B-cell activation and Ig secretion, and spontaneous production of a lymphokine [B-cell maturation factor (BMF)] that directly drives the maturation of normal or tumor B cells to the state of active Ig secretion. BMF from motheaten mice is distinct from previously identified forms in its cells of origin (B cells) and biochemical characteristics (apparent Mr 15,000 by gel filtration and NaDodSO4/PAGE; pI 4.3 by chromatofocusing). Among the known murine single-gene models of autoimmunity, only motheaten mice show high levels of spontaneous BMF production, which therefore may be an important component in the development of this form of autoimmunity/immunodeficiency disease. The coincidence of spontaneous BMF production and uncontrolled Ig secretion within the same mutant mouse constitutes the strongest evidence to date for a significant physiological (in vivo) role for BMFs.