Abstract: This study was designed to explore the protective effects of sildenafil and dipyridamole from toxicity of lead in an established model of rat liver perfusion. The rats were anesthetized with ketamine and chlorpromazine. The portal vein and the inferior vena cava were cannulated and the liver was perfused in situ through the portal vein with Krebs-Henseleit buffer. After 25 min of equilibration, lead (0.5 mM) and drugs (sildenafil 50 μM, dipyridamole 50 μM) were perfused for 45 min and samples of perfused fluid were collected for assessment of thiobarbituric reactive substances as index of lipid peroxidation. Lead treatment induced a marked lipid peroxidation. Cotreatment with sildenafil and dipyridamole significantly reduced lead-induced lipid peroxidation but did not reach control values. It is concluded that lead toxicity is mediated through lipid peroxidation in rat liver which is preventable with sildenafil and dipyridamole. This action of sildenafil and dipyridamole backs to their potential to increase intracellular cGMP which seems playing as an antioxidant.