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Background: Pentoxifylline (PEN) is a xanthine derivative with different functional characteristics including dilution of blood and increase in tissue oxygenation rate. Nitrosamines (NITs) are well known as strong carcinogenic agents. This study attempts to show the histopathological and biochemical effects of PEN against hepatotoxicity induced by NIT in rats. Methods: Sixty-four rats were assigned to eight groups including the groups of sham: NIT (40 mg/kg); PEN (25, 50, and 100 mg/kg); and NIT + PEN. Experimental treatments were applied either intraperitoneally (for NIT) or orally (for PEN) daily for 4 weeks. The relative expression level of p53 and Bax genes and hepatocyte apoptotic index were analyzed. Liver malondialdehyde (MDA), tissue ferric-reducing ability of plasma (FRAP), the diameters of hepatocytes (DH) and central hepatic vein (CHV), and biochemical liver function indicators (LFI) were investigated. Griess technique was hired for the determination of the level of serum nitrite oxide (NO). Results and Conclusions: NIT significantly increased the level of apoptotic gens and index, MDA, NO, diameter of CHV and DH, and LFI and decreased the FRAP level compared to the sham group (P < 0.01). All parameters in PEN and PEN + NIT groups significantly reduced (except FRAP level, which was decreased) in compared to the NIT group (P < 0.01) . By summarizing the results of this research, it is concluded that the PEN administration alleviates the hepatotoxicity due to oxidative stress produced by NIT in rats.