Transforming growth factor-beta 1 (TGF-beta 1) plays an important role in the pathogenesis of multiple malignancies, and its expression also strongly affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of TGF-beta 1 in melanoma patients. A total of 60 patients with a pathologically confirmed diagnosis of melanoma were enrolled into this study. Serum TGF-beta 1 concentrations were determined by the solid-phase sandwich ELISA method. Thirty age- and sex-matched healthy controls were included in the analysis. The median age at diagnosis was 53.5 years (range 16 to 88 years). The baseline serum TGF-beta 1 levels of the melanoma patients were significantly higher than those in the control group (median values 171.85 vs. 19.95 pg/mL, respectively; p < 0.001). The known clinical variables including age of patient, gender, site of lesion, histology, stage of disease, and serum LDH levels were not found to be correlated with serum TGF-beta 1 concentrations (p > 0.05). However, the chemotherapy-responsive patients had higher serum TGF-beta 1 levels compared with chemotherapy-unresponsive ones (p = 0.05). Additionally, serum TGF-beta 1 concentration was a trend to have a prognostic role on survival (p = 0.07). Patients with elevated serum TGF-beta 1 concentrations had close to significantly favorable overall survival compared to those with lower levels (median 30.1 vs. 20.9 months, respectively). In conclusion, serum levels of TGF-beta 1 have diagnostic, predictive, and possible prognostic roles in melanoma patients.