Abstract： Objective:To investigate the effect of hyperbaric oxygen（HBO）on enhancing the drug sensitivity of esophageal cancer cell line ECA109 to paclitaxel（Pac）and its mechanism of action.Methods:After the in vitro culture of esophageal cancer ECA109 cells was completed，the cells were divided into four groups according to the experimental design：the control group，the Pac group，the HBO group，and the HBO + Pac group. The control group received Dimethyl sulfoxide；the Pac group received 5 mg/L of Pac（referring to the IC 50 value）；the HBO group was exposed to HBO alone for 90 minutes；the HBO + Pac group was exposed to HBO for 90 minutes first and then treated with 5 mg/L of Pac. The proliferation ability of ECA109 cells was detected by the CCK-8 method，the apoptosis of ECA109 cells was detected by flow cytometry，and the expressions of apoptotic proteins，drug resistance-associated proteins，and mitogen-activated protein kinase（MAPK）signaling pathway-associated proteins in ECA109 cells were detected by Western blotting. Results:Compared with the control group and the HBO group，the survival rate of ECA109 cells in the Pac group was significantly decreased，and the apoptosis rate was significantly increased（ P<0.05）. Compared with the Pac group，the survival rate of ECA109 cells in the HBO + Pac group was significantly decreased，and the apoptosis rate was significantly increased（ P<0.05）. Compared with the control group and the HBO group，the expressions of proteins（Bcl-2，caspase-9，and ERK）in ECA109 cells of the Pac group and the HBO + Pac group were significantly decreased（ P<0.05），and the expressions of proteins（Bad，caspase-3，PARP，p-JNK，and p38）were significantly increased（ P<0.05）. Compared with the Pac group，the expressions of proteins（Bad and caspase-3）in ECA109 cells of the HBO + Pac group were significantly increased，and the expression of protein P-gp was significantly decreased（ P<0.05），while the expressions of proteins（Bcl-2，caspase-9，and PARP）were not significantly changed（ P>0.05）. Conclusion:HBO combined with Pac treatment can enhance the proliferation inhibitory and apoptosis-inducing effects of Pac on ECA109 cells，and its mechanism of action may be achieved by regulating the MAPK signaling pathway in ECA109 cells.