• The best combination and schedule for dacarbazine and melphalan with the Harding-Passey melanoma in C3D2F1 mice is achieved when dacarbazine is administered first, followed by melphalan, given on either the day of dacarbazine therapy or the first three days after dacarbazine is given. When dacarbazine is given first, followed by melphalan on day 0,1, 2, or 3, the effect of the two drugs is considerably more than additive. Other schedules reduce the outcome to a simple additive effect, or to an outcome that is less than additive, in which the combination is less effective than melphalan used alone. The effect of variations in the order and schedule of drug administration should be investigated in future trials of cancer chemotherapeutic agents, since profound effects may occur with these variations. (Arch Surg 114:135-138, 1979)