Grape seed proanthocyanidin extract (GSPE) is known to be effective on broad spectrum of biological pathways in living organisms including oxidative stress. The present study aimed to investigate the effects of proanthocyanidin on preneoplastic lesions and liver cancer induced in rats by Diethylnitrosamine (DEN). 7–8 Week old male Sprague Dawley (S.D.) rats were divided into six groups: The 1st group received no treatment and were −ve controls, the 2nd were treated with a single dose of DEN 200 mg/kg intraperitoneally (i.p.) and served as +ve control group. The 3rd and 4th groups were injected with the same dose of DEN as in group 2 and then post treated with 300 or 150 mg/kg/b.wt./day GSPE by intrgastroluminal gavage (i.g.) respectively until the end after the 22 weeks. Groups 5 and 6 were treated with the same doses of GSPE as in groups 3 and 4 respectively without DEN administration. The results showed that the immunohistochemical Proliferating Cell Nuclear Antigen (PCNA) labeling indexes (PCNA LI%) were significantly inhibited in liver tissues and tumors by both treatments of GSPE. Furthermore, treatment with GSPE has modified the liver tissue oxidative stress markers levels of SOD, CAT, GSH, GST, GPx, GR and MDA changed by DEN. In conclusion, GSPE has a sufficient therapeutic effect against liver carcinogenesis through their free radical scavenging, inhibition of cellular proliferation.