The incidence of melanoma is increasing worldwide. Prognosis for metastatic melanoma is poor; early detection of recurrent or metastatic disease may improve therapy strategies and survival. Several possible biomarkers for melanoma have been investigated. S-100B was found to be a sensitive and specific serological tumor marker; furthermore, its con-centrations are correlated with the clinical stage of disease. Serum S-100B is also an inde-pendent prognostic factor for survival and can be used to monitor response to treatment. We present the case of a 55 year old woman, whose diagnosis of melanoma distant me-tastases was suggested by a progressive increase in serum S-100B levels, while other blood tests, physical exam and imaging techniques, including PET/TC and CT-scan, were negative. S-100B is currently the most accurate biomarker in melanoma patients; its role in the management of melanoma patients has been the object of study and it has been documented as a valuable independent prognostic factor. The case we present shows that S-100B levels may also be useful in the early detection of melanoma recurrences, even when imaging techniques are negative.