The authors evaluated the records of 371 patients with metastatic melanoma who received treatment with high-dose bolus interleukin-2. Patients with metastases only at cutaneous or subcutaneous sites had a higher objective response rate (50%) than did patients with metastases at these sites plus visceral sites (14%) or patients with metastases at visceral sites only (13%) (p<0.0001). Five patients with disease at cutaneous or subcutaneous sites plus visceral sites experienced regression only at the cutaneous or subcutaneous sites with progression at the visceral sites. Therefore, in the presence of visceral disease, the response rate at cutaneous or subcutaneous sites was only 17% compared with 50% when disease was at the latter sites only (p<0.001). These data suggest that melanoma lesions at cutaneous or subcutaneous sites are highly susceptible targets to interleukin-2–based therapies, but the presence of visceral disease is associated with a significant inhibition of response at cutaneous or subcutaneous sites.