We report 16 cases of metastatic malignant melanoma presenting clinically as lymphadenopathy or a soft-tissue mass and histologically resembling malignant peripheral nerve sheath tumor (MPNST). In two cases, the metastatic malignant melanoma was preceded by a primary cutaneous malignant melanoma; in four cases, it presented synchronously with such a tumor; and in 10 cases, there was no evidence of a previous or concomitant malignant skin lesion. Histologically, the tumors were characterized by a malignant-appearing spindle cell proliferation arranged in fascicles, often accompanied by a peritheliomatous growth pattern, alternating hypercellular and hypocellular areas, numerous mitoses, and foci of necrosis. In nine cases, there was residual lymph node tissue. In none of the cases was there evidence of an anatomic connection with a nerve, a coexistent neurofibroma, or the stigmata of neurofibromatosis. Fourteen of the cases showed strong and generally diffuse immunoreactivity for S-100 protein, and five cases showed positivity for HMB-45. Four of eight patients with follow-up information died of the disease. Tumors with a microscopic appearance compatible with MPNST but showing strong diffuse S-100 protein staining and featuring remnants of lymph node may represent metastatic malignant melanomas and should elicit a search for a previous or concomitant tumor in the skin and other sites. The similarities these tumors share with MPNST are probably related to their common neuroectodermal histogenesis.