Most patients with common variable immunodeficiency (CVI) have normal numbers of circulating B cells but low concentrations of serum Ig. To determine if the hypogammaglobulinemia is caused by an intrinsic B cell defect, we studied B cell function of 22 CVI patients. Cultured B cells from all CVI patients underwent normal proliferation and synthesized normal quantities of IgE in the presence of anti-CD40 and IL-4. If cultured with anti-CD40 and IL-10, four patterns of Ig isotype synthesis were observed. Six CVI patients produced normal amounts of IgM, IgG, and IgA. Four patients produced normal quantities of IgM and IgG. Of the remaining 12 patients who failed to synthesize IgG and IgA, 8 produced normal and 4 synthesized decreased amounts of IgM. Analysis of the IgG subclasses produced by 10 patients with IgG-secreting B cells revealed that IgG4 was the most affected subclass, followed by IgG2; synthesis of IgG3 and IgG1 remained normal. Similarly, in the six IgA producing patients, IgA2 was more often affected than IgA1. The hierarchy of Ig isotype and subclass synthesis corresponds to Ig heavy chain constant region gene location on chromosome 14. Thus, circulating B cells of CVI patients are committed to synthesize one or more Ig isotypes or subclasses, and under proper conditions can proliferate, mature into Ig-secreting cells, and undergo class switch to IgE.