The effect of cyclophosphamide (CTX) on the renal handling of water and sodium and on plasma concentrations of vasopressin (AVP) and of the atrial natriuretic factor (ANF) was studied in the rabbit. When compared to controls, animals receiving CTX (100 mg/kg IV) showed an increase in the diuresis and natriuresis. In addition, ANF plasma concentrations increased by 84% between 4 and 8 hours after CTX, while AVP plasma concentrations remained unchanged. It is concluded that in the rabbit CTX has a diuretic and a natriuretic effect that may, at least in part, be related to the increase in ANF plasma concentrations.