Purpose: To examine the effect of zinc protoporphyrin IX (ZnPPIX) on the sensitivity of colorectal cancer (CRC) cells to paclitaxel. Methods: Paclitaxel-resistant CRC cells were established by incubating CRC cells with increasing concentrations of paclitaxel. Colorectal cancer cells were incubated with ZnPPIX for 1 h before treatment with paclitaxel. Cell viability, proliferation, and apoptosis were determined by MTT, colony formation, and flow cytometry assays, respectively. The effect of ZnPPIX on DNA damage response in paclitaxel-resistant cells was assessed using western blot analysis of gamma H2AX, p-DNA-PK, and Rad51. Results: Paclitaxel suppressed proliferation of SW480 cells at an IC50 (half-maximal inhibitory concentration) of 0.23 mu M, while that of proliferation of paclitaxel-resistant SW480 cells was also suppressed by paclitaxel at an IC50 of 2.58 mu M (p < 0.05). Incubation with ZnPPIX attenuated the paclitaxel-induced decrease in viability and proliferation of SW480 cells. Paclitaxel-induced apoptosis of SW480 cells was enhanced upon incubation with ZnPPIX (p < 0.05). Similarly, protein expression of gamma H2AX was enhanced while protein expressions of p-DNA-PK and Rad51 reduced in paclitaxel-induced SW480 cells. On incubation with ZnPPIX, protein expression of heme oxygenase-1 (HO-1) and AKT and mTOR phosphorylation decreased in SsW480 cells (p < 0.05). Conclusion: ZnPPIX enhances paclitaxel-induced chemosensitivity of CRC by suppression of HO-1mediated AKT/mTOR activation, and could potentially be used to facilitate the management of CRC.