The incidence of skin cancer has increased dramatically in recent decades, particularly melanoma. In this study, the cytotoxic effects of sodium dichloroacetate (DCA) in combination with chemotherapeutic drugs such as doxorubicin (DOX) and cisplatin (CIS) were evaluated. In vitro, B16F10, macrophages, and murine erythrocytes were treated with DCA (ranged from 3.66 × 104 to 3.66 × 105 μmol/L), DOX (1.38 × 10-4 to 1.38 × 10-3 μmol/L) and CIS (0.16 to 1.28 μmol/L) alone or in combination and were incubated for 72 h. Cell viability and hemolysis were determined by the MTT method and released hemoglobin, respectively. The results obtained on B16F10 cells indicate that the treatment with DCA alone showed a half-maximal inhibitory concentration (IC50) of 1.49 × 105 μmol/L, DOX caused an IC50 of 1.12 × 10-4 μmol/L and CIS-induced an IC50 of 1.14 μmol/L. Combinations of treatments with IC50 of DCA+CIS or DCA+DOX resulted in significantly decreased cell viability by 60 and 95%, respectively. Finally, the treatments alone or in combination did not cause lysis of murine erythrocytes and did not affect the cell viability of macrophages. Our results suggest that DCA enhances cytotoxicity induced by CIS or DOX on B16F10 cells without affecting erythrocytes and macrophages integrity.