【Abstract】 Objective To determine the effect of autophagy on the apoptosis of hepatocellular carcinoma cells induced by arsenic trioxide (ATO). Methods Hepatocellular carcinoma HepG2 cells were exposed to ATO. The cell viability was detected by MTT after adjustments for autophagy agonist (Rap) and autophagy inhibitor (3-MA). The autophagosome was observed under electronic microscope. The autophagy related proteins (LC3 and Beclin1) were detected by immunofluorescence. The cell apoptosis was measured by flow cytometry. Results With 5-20 μmol/Lof ATO, HepG2 cells exposed to 3-MA had significantly lower viability (P P 20 μmol/Lof ATO, the cells exposed to Rap showed significantly higher viability (P P P >0.05). Conclusion Targeted autophagy inhibition can significantly increase the sensitivity of HepG2 to ATO. The underlining mechanism is associated with enhanced apoptosis of hepatocellular carcinoma cells.