Background: phenytoin is one of the most commonly used anticonvulsants for treating generalized tonic-clonic seizures and status epileptics. Rosuvastatin is a new generation HMG-CoA reductase inhibitor. This enzyme converts HMG-CoA to mevalonic acid in the cholesterol biosynthetic pathway which is the rate limiting step in cholesterol synthesis.  Aim: This study was aimed to investigate the possible interactions between phenytoin and rosuvastatin when used together in irradiated rats. Methods: The experiments were carried out to investigate the acute effect of each drug individually and in combination with radiation on lipid profile [ Total cholesterol, Triacylglycerols, High density lipoproteins, Low density lipoproteins and Very low density lipoproteins, Risk factor, Atherogenic Index], liver function tests (AST & ALT) and oxidative stress biomarkers (MDA, NO & SOD). Results: Data revealed that, phenytoin in irradiated rats significantly increased serum total cholesterol compared to normal control. Rosuvastatin significantly decreased serum total cholesterol compared to irradiated control. Combination of two drugs significantly increased serum total cholesterol; triacylglycerols and serum VLDL-c levels compared to normal and irradiated rats and significantly increased Atherogenic Index and Risk factor compared to normal control. Phenytoin significantly increased serum ALT level compared to normal and irradiated rats and significantly increased serum MDA and serum NO levels compared to normal rats. But phenytoin significantly decreased MDA & NO levels and significantly increased SOD activity compared to irradiated rats. Rosuvastatin significantly increased serum ALT level compared to normal control but it significantly decreased MDA and significantly increased SOD activity compared to irradiated rats. Combination phenytoin and rosuvastatin in irradiated rats significantly increased serum ALT level compared to normal and irradiated rats and it significantly increased MDA, NO levels but it significantly decreased SOD activity compared to normal control.  It could be concluded that administration of phenytoin concurrently with rosuvastatin not recommended in patients receiving radiotherapy as dangerous side effects may be occurred.