Biomarkers are strongly needed for diagnostic surveillance of patients with metastatic melanoma. On the basis of its known association with tumor metastasis and its ability to induce cancer cachexia, we investigated serum levels of growth and differentiation factor 15 (sGDF-15) as a marker for overall survival (OS). sGDF-15 was retrospectively measured by ELISA in 761 samples obtained at distinct time points during routine clinical care of patients with stage III/IV melanoma. In the entire cohort, sGDF-15 ≥ 1.5 ng/ml was strongly associated with reduced OS after assessment. Subsequent analyses were performed separately for tumor-free stage III, tumor-free stage IV, and unresectable stage IV patients. For patients with unresectable distant metastasis (n = 206), sGDF-15 was independently associated with OS when considered together with the M-category and superior to serum level of lactate dehydrogenase. Analysis in tumor-free stage III patients during routine surveillance (n = 468) revealed sGDF-15 to be associated with OS and an independent factor when considered together with S100B and the pattern of locoregional metastasis. Only in tumor-free stage IV patients (n = 87) sGDF-15 was not associated with OS. sGDF-15 should thus be further validated as a marker for early detection of recurrence in stage III patients and as a prognostic or predictive marker particularly in the context newly available treatments in unresectable stage IV patients.