TO ACHIEVE THE HIGH DRUG CONCENTRATIONS IN A TARGET TISSUE (TUMOR) WITH MINIMAL DRUG LEVELS IN ORGANS NOT INVOLVED BY CANCER, THEREBY AVOIDING SERIOUS SYSTEMIC SIDE EFFECTS, THREE METHODS OF ADRIAMYCIN ADMINISTRATION: 1) Isolation perfusion, 2) Intra-arterial infusion, and 3) Intravenous infusion were studied in 22 dogs. Latter two methods were studied in several patients with soft tissue sarcoma of the extremities. Isolation perfusion of the hind extremity was done through the femoral vessels; intra-arterial and intravenous infusions were done through the femoral artery and cephalic vein, respectively. Adriamycin levels in tissues of the hind extremity and blood were determined. The highest Adriamycin levels in tissues could safely be achieved by isolation perfusion. Drug concentrations in regional tissues were not significantly different after intra-arterial infusion as compared to those after intravenous infusion. Much of the drug went into systemic circulation after intra-arterial infusion and almost none after isolation perfusion. Hematologic and histologic evidence of lethal systemic toxicity was noted only in dogs receiving Adriamycin by infusions. Edema, patchy muscle necrosis, hemorrhages, and skin ulcerations were observed in the perfused extremities only. In human studies, drug levels in blood were comparable to those in animal study when Adriamycin was administered by the latter two methods.