Abstract: Objective To explore the effect of PEGylation of α-Momorcharin (α-MMC), one of ribosome-inactivating proteins from bitter melon seed, against its hepatotoxicity in rats. Methods SD rats were randomized into NS group, α-MMC treated groups, and α-MMC-PEG treated groups. The doses of α-MMC and α-MMC-PEG were high, middle, and low dose(6.25, 2.08, 0.70 mg/kg). The rats were given different dose of α-MMC, or α-MMC-PEG via caudal vein every other day for consecutive 28 days and then left for 14 days recovery. The general condition of animals was observed, blood and liver samples were collected for liver function study and pathological examination on day 28 after initiation of administration and on day 14 after withdrawal. Results On day 28 after initiation of administration, the liver function damages were found in high-dose and middle-dose of α-MMC treated groups, such as the decreasing of ALB, increasing of GLB, A/G ratio decreasing and the dose-dependant increasing of AST, BIL and CHO. The pathological changes of hepatotoxicity were also observed in these two groups, including the massive hepatocyte, swelling degeneration, inflammatory cell infiltration, congestion and diffusive necrosis. However, the liver function and pathological changes in α-MMC-PEG treated groups were better than those in α-MMC treated groups. Conclusion PEGylation could reduce the hepatotoxicity of α-MMC to rats.