Recently, it was reported that soluble MICB (sMICB) may impair tumor immunogenicity by reducing natural killer group 2D ligand densities on malignant cells. The aim of this study was to elucidate the role of sMICB in melanoma patients. In the present study, we determined sMICB serum concentration in 125 melanoma patients of different clinical stages of disease compared with 30 healthy controls using an ELISA. The correlations between sMICB serum concentration and clinicopathologic variables were analyzed. sMICB serum level was significantly elevated (P < 0.0005) in melanoma patients (mean ± SE = 8.60 ± 0.26 ng/ml) compared with healthy controls (mean ± SE = 6.27 ± 0.25 ng/ml). Univariate analysis revealed a correlation of sMICB serum concentration with advanced stages of disease (P = 0.009). Only a slight increase in sMICB serum level (P = 0.057) could be observed in regard to the tumor burden. Patients undergoing current treatment with cytostatics (n = 18) revealed a strong increase in sMICB serum level (P < 0.0005), whereas treatment with IFN-α alone or combined with cytostatics (n = 19) showed no change in serum sMICB concentration. According to Kaplan-Meier analysis, elevated sMICB serum levels were associated with a poor overall and a progression-free survival. Multivariate analysis revealed sMICB serum concentration as an independent predictive factor for progression-free and overall survival. Our results show a prognostic relevance of serum sMICB in melanoma patients, indicating that the evaluation of sMICB serum level may be important for the selection of therapeutic strategies.