The authors have used imidazole carboxamide (DTIC) in vascular isolation and hyperthermic perfusion for melanoma. The regional and systemic toxicity and complications of this procedure were studied in 40 cases with Stage III (15) and Stage I (25) melanoma. Technetium 99m-labelled serum albumin crossover and pharmacokinetic studies were done simultaneously to see if these correlate with toxicity. Local toxicity on muscles, nerves, skin, and arteries was conspicuously absent despite using dosages of 2 g/m2 (40-45 mg/kg) for the lower extremity and 1.2 g/m2 (24-28 mg/kg) for the upper extremity. Skin and core temperature were raised to 39 degrees C to 40 degrees C. Deep vein thrombosis was noted in three patients. No death or gangrene of the extremities occurred. Local infection was noted in only one patient. Fourteen patients (35%) manifested bone marrow toxicity (leukocyte count of 4000/mm3 or platelets of 100,000/mm3) in the second or third week after perfusion. Severe hematologic toxicity was seen in two instances. Dosages of DTIC greater than 40 mg/kg were associated with toxicity in 65% of the patients. No bleeding complications occurred in seven patients with thrombocytopenia. Measurement of crossover and recovery of radionuclide were not reliable indicators of subsequent systemic toxicity. Perfusion fluid balance data also were of no predictive value. Forty-seven percent of the administered DTIC was recovered in washout fluid. Of this, less than 2% was converted to its metabolites, that is aminoimidazole carboxamide and 2-azahypoxanthine. Thirty-five of 40 patients experienced mild nausea and vomiting. Transient and mild hepatotoxicity was noted in seven patients. It appears that DTIC hyperthermic isolation perfusion is a safe procedure, however, the total dosage should be below 40 mg/kg to avoid hematologic toxicity.