(1) Background: Cutaneous melanoma (CM) originates from melanocytes and causes 90% of skin cancer deaths; therefore, the comparison of different soluble and tissue markers could be valuable in the detection of melanoma progression and therapy monitoring. The present study is focused on the potential correlations between soluble S100B and MIA protein levels in different melanoma stages or with tissue expression of S100, gp100 (HMB45), and MelanA biomarkers. (2) Methods: Soluble S100B and MIA levels were evaluated by means of immunoassay methods in blood samples from 176 patients with CM, while tissue expressions of S100, MelanA, and gp100 (HMB45) were detected by means of immunohistochemistry in 76 melanomas. (3) Results: Soluble S100B correlated with MIA in stages III (r= 0.677,p< 0.001) and IV (r= 0.662,p< 0.001) but not in stages I and II; however, 22.22% and 31.98% of stage I and II patients, respectively, had high values for at least one of the two soluble markers. S100 tissue expression correlated with both MelanA (r= 0.610,p< 0.001) and HMB45 (r= 0.476,p< 0.01), while HMB45 and MelanA also significantly positively correlated (r= 0.623,p <0.001). (4) Conclusions: Blood levels of S100B and MIA corroborated with melanoma tissue markers expression could help to improve the stratification process for patients with a high risk of tumor progression.