Objective：A major problem in the chemotherapy of colon caner may be due to those cells that are in residence in the G0 phase where they are less vulnerable to conventional therapy. To overcome this phenomenon, we attempted to recruit the reentry of these cells into the cell cycle via a signaling pathway that manipulates tumor growth. Methods: Epidermal growth factor (EGF) was used to stimulate colon cancer caco-2 cells. FACS analysis and proliferating cell nuclear antigen (PCNA) staining were used to estimate the cell cycle transition and cell proliferation activated by EGF, and a MTT assay was used to evaluate the synergistic effect of EGF and chemotherapy. Results: The percentage of caco-2 cells in the G0/G1 phase was significantly reduced by nearly 20% and the percentages in the S and G2/M phases were increased by EGF. The combined use of EGF and 5-fluorouracil (5-FU) enhanced the caco-2 cell chemosensitivity to 5-FU, reaching a maximum of an approximately threefold greater sensitivity than to 5-FU alone as judged by the 50% inhibiting concentration (IC50). Conclusion: Our study demonstrated that stimulation by EGF enhanced the chemosensitivity of caco-2 cells to 5-FU, which may be a novel therapeutic protocol in colon cancer.