A feasibility study was conducted to establish the safety and, to some extent, the effectiveness of a new approach of perioperative adjuvant biotherapy in patients with resected cutaneous melanoma. The candidates for this study included patients with primary cutaneous melanoma greater than 1 mm deep, those with resectable regional lymph node (LN) metastases and patients with resectable distant metastases. Interleukin-2 was administered 1 week before definitive surgery as 22 million IU, and again 1 week after the surgery. This was followed by interferon alpha-2b, 10 million IU three times a week for 4 weeks. Fifty-six patients were studied. The program was well tolerated with low, mainly symptomatic, grade I-II toxicity, occasionally with grade III toxicity. Patients' compliance was good. The 5-year survival data were expressed by Kaplan-Meier analysis, and compared with matched historical controls by the log-rank method. The results suggested an improvement in disease-free survival (P=0.021) and a disease-specific overall survival (P=0.05), but not in overall survival, owing to all causes of death (P=0.089). The consequent administration of low-dose interleukin-2 and interferon, initiated preoperatively on outpatient bases, resulted in several constitutional symptoms that were self-limiting and did not delay surgery. No surgical complications related to this approach were observed. This program was well tolerated in all age groups, and the results suggested some survival benefits when compared with matched historical controls.