S-100 protein and neuron-specific enolase (NSE) have recently been proposed as serum markers for melanoma. In this study NSE and S-100 serum levels were assayed by commercial IRMA methods in 53 patients with melanoma. The overall prevalence of abnormal marker levels was similar for NSE (26%) and S-100 (30%). The 24 patients in stages I and II had uniformly normal S-100 levels, but abnormal NSE levels were observed in 3 out of the 12 patients in stage II (33%) and in 1 out of 12 in stage I. NSE appears thus to be the marker of choice in the early stages, where its increase points to disease progression. In patients in stages III and IV the prevalence of abnormal values was 34% for NSE and 55% for S-100 (p = < 0.05). In the latter group diagnostic sensitivity increased to 62% if isolated elevation of each marker was considered. In patients with advanced stage disease, both NSE and S-100 should be assayed.