Despite of highly effective new therapeutic strategies, chemotherapy still is an important treatment option in metastatic melanoma. Since predictors of chemotherapy response are rare, drugs and regimens are currently chosen arbitrarily. The present study was aimed at the identification of molecular markers predicting the outcome of chemotherapy in melanoma. Tumor biopsies from metastatic lesions were collected from 203 stage IV melanoma patients prior to chemotherapy onset and used for gene expression profiling (n = 6; marker identification set), quantitative real-time PCR (n = 127; validation set 1), and immunohistochemistry on tissue microarrays (n = 70; validation set 2). The results were correlated to the tumors' in-vitro chemosensitivity and to the patients' in-vivo chemotherapy outcome. SERPINB1 was found to correlate to the in-vitro sensitivity to cisplatin-containing chemotherapy regimens (p = 0.005). High SERPINB1 gene expression was associated with favorable tumor response (p = 0.012) and prolonged survival (p = 0.081) under cisplatin-based chemotherapy. High SERPINB1 protein expression in tumor tissue from cisplatin-treated patients was associated with a favorable survival (p = 0.011), and proved as an independent predictor of survival (p = 0.008) by multivariate analysis. We conclude, that SERPINB1 expression, although not functionally involved, is predictive for the outcome of cisplatin-based chemotherapy in melanoma, and thus may be useful to personalize melanoma chemotherapy.