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Cyclocreatine (CCr), a substrate analogue of creatine kinase (CK: EC 2.7.3.2.), exhibits anti-tumor activity in vitro and in vivo. We examined the effects of CCr on the hepatocarcinogenesis of F344 rats caused by treatment with diethylnitrosamine (DEN), partial hepatectomy (PH) or 2-acetylaminofluorene (2-AAF). The rats were given a single intraperitoneal injection of 200 mg of DEN per kg in 0.85% NaCl solution at four weeks of age. Two weeks later they were divided into two groups. One group was continuously fed a commercial powder diet containing 0.02% 2-AAF for 12 weeks and the other was continuously fed a commercial powder diet containing 1% CCr plus 0.02% 2-AAF for 12 weeks. A third group of rats as a control was given only a normal powder diet for 12 weeks. All the groups were subjected to a two-thirds partial hepatectomy (PH) at 3 weeks under avertin anesthesia. To elucidate the inhibitory effect of CCr on chemical induced hepatocarcinogenesis, we examined not only the distribution of glutathione-S-transferase placental form (GST-P) a marker used for tumorigenesis, but also the inhibition of the degree of apoptosis. The number (No./cm2) and area (mm2/cm2) of GST-P positive liver foci were significantly lower in the 2-AAF + CCr treated when compared to the group treated with 2-AAF only. Our data suggest that CCr inhibits the degrees of GST-P-positive cells and apoptosis and is active against hepatocarcinogenesis in rat models. This result points out the unique nature of an anticancer agent that inhibits progression of chemically induced hepatocarcinogenesis of rats.