Background: CD200 is an immunosuppressive glycoprotein known to have pro-tumor properties. Cyclooxygenase-2 (COX-2), plays a role in the carcinogenesis in solid organ tumors. Objectives: We evaluated CD200 and COX-2 protein expression and their correlation in melanoma tissues and determined their effects on clinicopathological characteristics and biological responses in melanoma. Methods: Diagnostic tissue from 118 cases of melanoma was evaluated by immunohistochemistry for CD200 and COX-2 expression. Clinicopathological features and survivals were analyzed according to CD200 and COX-2 expression. BRAFV600E A375 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on CD200 expression in vitro. Results: CD200 expression was positively correlated with COX-2 expression in melanoma tissue. CD200 and COX-2 expression was significantly associated with negative prognostic factors: deeper Breslow thickness, vertical growth phase, lymph node involvement, and advanced stage of melanoma. CD200 and COX-2 were also found to be independent prognostic indicators of a poorer overall survival. The inhibition of COX-2 activity by celecoxib downregulated CD200 expression in BRAFV600E melanoma cell lines. Conclusion: Expression of CD200 represents an independent unfavorable prognostic factor in melanoma. CD200 expression is correlated with COX-2 and could be downregulated by COX-2 inhibition.