Fibronectin and vitronectin are the important components of the extracellular matrix proteins. The aim of this study was to determine the clinical significance of these protein serum levels in patients with melanoma. A total of 60 patients with a pathologically confirmed diagnosis of melanoma were enrolled in this study. Serum fibronectin and vitronectin concentrations were determined using the solid-phase sandwich ELISA method. Thirty age-matched and sex-matched healthy controls were included in the analysis. The baseline serum fibronectin and vitronectin levels were significantly higher in patients with melanoma than those in the healthy control group (P<0.001 and P=0.04, respectively). However, known clinical variables including age of the patient, sex, site of lesion, histology, stage of disease, serum lactate dehydrogenase levels, and response to chemotherapy were not found to be correlated with either serum fibronectin or vitronectin concentrations (P>0.05). Moreover, neither serum fibronectin nor vitronectin levels played a prognostic role in outcome in melanoma patients (P=0.47 and 0.24, respectively). In conclusion, serum levels of both fibronectin and vitronectin may be diagnostic markers in melanoma patients. However, their predictive and prognostic values were not determined.