The immunologic defect in X-linked immunodeficiency and hyperimmunoglobulinemia M (HIM) are related to defective expression of the CD40 ligand (CD40L). We have studied two female patients with HIM to evaluate the role of CD40/CD40L in the pathogenesis of impaired immunoglobulin switching. In addition to recurrent infections characteristic of humoral immunodeficiencies, the two patients had chronic hepatitis caused by type C virus. Phenotypic characterization of peripheral blood mononuclear cells showed a similar picture in both patients, with a reduction in the absolute numbers of CD4 cells and increased numbers of CD8 and CD3/DR cells. B cells (CD19+) were reduced in one patient, but CD40 was expressed on all CD19+ cells in both patients. The expression of CD40L was normal on peripheral blood mononuclear cells from the two patients with HIM on both resting and stimulated cells. The combination of anti-CD40 and cytokines (interleukin-2, interleukin-4, and interleukin-10) was able to restore proliferative capacity to anti-IgM. Peripheral blood mononuclear cells from the two patients with HIM showed a high spontaneous production of IgM in vitro and no production of IgG or IgE. Our data suggest that the defect of isotype switching in female patients with HIM is not related to defective expression of the CD40/CD40L receptor system. A possible role for chronic hepatitis C virus infection in the pathogenesis of the disease is suggested by the detection of specific production of anti-hepatitis C virus IgM. (J ALLERGY CLIN IMMUNOL 1995;96:403-10.)