The immune responses of 16 patients with nonneoplastic immune mediated diseases including Wegener's granulomatosis, systemic necrotizing vasculitis, cutaneous vasculitis, and relapsing nodular panniculitis were evaluated before and during therapy with chronic low-dose (2 mg/kg/day) cyclophosphamide. A striking selective suppression of B cell function was noted as measured by PWM-induced immunoglobulin secretion. This suppression was a direct effect on the B cells themselves because T cell function, measured by blastogenic responses to the mitogens PHA, Con A, and PWM, was not significantly suppressed. Furthermore, the ability of T cells from cyclophosphamide-treated patients to provide helper function in T cell-dependent B cell assays remained intact. Treated patients manifested a total lymphocytopenia without a selective depletion of relative proportions of B cells or T cell subsets. However, the spontaneous secretion of immunoglobulin by peripheral blood B cells that is elevated in untreated patients was suppressed back to normal levels during cyclophosphamide therapy. This selective effect on spontaneous and induced secretion of immunoglobulin by human B cells may help explain the efficacy of cyclophosphamide therapy in certain antibody and immune complex-mediated diseases.