We investigated the immunomodulatory effect of cyclophosphamide on the induction of suppressor cell activities in peripheral blood lymphocytes. The sera from advanced breast cancer patients as well as concanavalin-A (Con-A) induced suppressor cell activities in lymphocytes from healthy volunteers. Pretreatment of these lymphocytes, including CD4+ T cells with 4-hydroperoxycyclophosphamide (4-HC), an active form of cyclophosphamide, abrogated the induction of suppressor cell activities by either cancer sera or Con-A. A decrease in CD4+CD45RA+ suppressor/inducer T cells and reduction of Con-A induced suppressor cell activities were observed in breast cancer patients with metastases that were treated with cyclophosphamide (CPM). These results suggest that cyclophosphamide may modulate the immune responses of breast cancer patients by interference with suppressor/inducer T cells.