Background: Early detection of melanoma recurrence is essential for the patient’s prognosis. The serum S100 level may be a useful tool to detect relapse early. Objective: To compare the efficacy of imaging techniques and serum S100 in the early detection of melanoma progression. This is the first report of a comparison of a serum marker with an imaging tool in the follow-up of melanoma patients. Methods: From 1992 to 2003, we screened 192 patients suffering from melanoma recurrence after a disease-free interval. Of those, 127 patients were identified whose S100 levels had been assessed parallel to imaging procedures. Results: Serum S100 was elevated in 37% of patients at the time of relapse. In stage III, 32% of the patients had elevated S100 levels whereas in case of progression to stage IV, 48% of the patients presented with increased S100. In 5.5% of patients, S100 was the first indicator of disease progression. Imaging procedures lead to detection of melanoma recurrence in 26.8%. Conclusion: A rising level of serum S100 is a specific and sensitive marker of melanoma progression.