S-100, an acidic calcium-binding protein, is present within cells of neuroendocrine origin. Its value in the immunohistochemical diagnosis of tumours of melanocytic origin is well established. More recently, a potential role has been proposed for the serum concentration of this protein as a marker of metastatic melanoma disease activity. In the present study, the concentration of serum S-100 protein was measured in 97 patients with histologically proven malignant melanoma who were attending a dermatology and/or oncology department for the follow-up of their disease. Serum S-100 was also measured in 48 control subjects without malignant melanoma. The clinical stage of the patients was classified according to the criteria of the American Joint Committee on Cancer into stages I-IV. The median (range) serum S-100 protein concentration was significantly higher in stage I (0·11 (0·1–0·21) μg/L, P<0·001), stage II (0·11 (0·05–0·22) μg/L, P<0·001), stage III (0·24 (0·07–0·41)μg/L, P<0·0001) and stage IV (0·39 (0·06–15·0)μg/L, P<0·0001) compared with the control group (0·1 (0·05–0·15)μg/L). At a threshold value of 0·2μg/L, the sensitivity and specificity for detection of advanced disease were 82% and 91%. respectively. Thus serum S-100 protein may be a valuable prognostic marker for malignant melanoma and for monitoring therapy. Serum S-100 protein concentration was also compared with the Breslow thickness of the tumours. There was a significant correlation between these variables (n=72. rs=0·32, P<0·01). Combining a serum S-100 threshold value of >0·22μg/L and a Breslow thickness of >4mm improved the sensitivity and specificity for the presence of secondary spread to 91% and 95%, respectively. Therefore, a combination of both baseline serum S-100 protein and Breslow thickness may provide a better indication of the prognosis at diagnosis.