Background: Valproic acid (VPA) andcarbamazepine (CBZ), two widely used antiepileptic drugs, have recently been found to inhibit histone deacetylases (HDAC). HDAC inhibitors (HDACIs) have various effects on cancer cells. Objectives: The aim of this study was to compare the anticancer activity of these drugs on SW480 colon cancer cell lines. Methods: In the present experimental study, implemented during 2014 - 2015 in Iran, after incubation of cells into 96-well plates with 5,500 cells/well, the tested drugs were added, and cytotoxic effects were assessed by MTT. Moreover, after incubation of 8 x 10(6) cells in 75 cm(2) flasks to obtain beta-catenin levels and 106 cells in a six-well plate to obtain vascular endothelial growth factor (VEGF) levels, these levels were estimated using enzyme-linked immunosorbent assay (ELISA) analysis. Results: Through MTT assay, we found that the inhibitory concentration of 50% (IC50) values for VPA and CBZ were 2.5 mM and 5 mu M, respectively in comparison to controls in terms of total concentration and times evaluated (P < 0.0001). We also found that treatments with these drugs decreased levels of beta-catenin (P < 0.0001) and VEGF (P < 0.0001) significantly more than controls. Conclusions: VPA and CBZ treatments caused a decrease in beta-Catenin and VEGF levels in SW480 colon cancer cell lines. These results suggest that CBZ can be considered a potential antitumor drug with potencies different from VPA.