The effect of streptozotocin-induced diabetes in male Sprague—Dawley rats was investigated to ascertain whether it has had any modulating role in hepatocarcinogenesis. Hepatocarcinogenesis was initiated with a single sub-necrogenic dose of diethylnitrosamine (DEN) (125mg/kg body weight, i.p.) whilst acute diabetes was produced with a single i.p. injection of streptozotocin (STZ) (65mg/kg body weight). STZ was administered either before or after initiation with DEN at 3-week intervals. With this basic experimental regimen, the effect of an antioxidant vitamin, 1α, 25-dihydroxyvitamin D3(VD) (0.3μg/ 0.1ml propylene glycol per os twice a week), was investigated with effect from 4 weeks prior to the exposure of DEN or STZ. Primary routine histopathology, hepatic nodular morphometric analysis and major preneoplastic antioxidant and drug metabolising enzymes were tested either with or without VD treatment in different experimental and control groups. Observation of the hepatic nodulogenesis, pathology and level of the antioxidant and drug metabolising enzyme pattern of the tissue showed a marked protection in different experimental groups of rats treated with VD. It may be that VD could elicit an anticarcinogenic potential in the aforesaid regimen by resetting the effects of these biomarkers induced by DEN and/or STZ. We further propose that STZ, when administered 3 weeks after DEN, caused massive damage where its action in vivo could be comparable with any known promoter that could propel the process of carcinogenesis more efficiently than when it was applied before the carcinogen.