Patients with hypertension take antihypertensive agents and cholesterol-lowering drugs; however, few studies describe the effects of the interaction of antihypertensive agents with statins. Therefore, the purpose of this study was to characterize the effects of losartan, simvastatin, and their combination on the progression of hypertension in the spontaneously hypertensive rats (SHRs). Also, we determined whether diet influenced the drug responses. Rats were fed three different diets - low-salt (LS), high-salt (HS), and lipid-rich (LR) - and treated with either no drug (control), losartan (LOS, 10 mg/kg/day), simvastatin (SIM, 2 mg/kg/day) or LOS combined with SIM for four weeks. After four weeks on the diets, systolic blood pressure rose in all groups and remained elevated. Treatment with LOS alone or in combination with SIM reduced BP in the rats fed the LS and HS diet, respectively. Furthermore, LOS alone increased NO in the LS and LR groups; however, LOS combined with SIM completely abolished this rise in NO in LS group. Plasma PGI2 and TXA2 levels were increased in the presence of SIM alone; however LOS combined with SIM completely blocked SIM-induced increases in PGI2 and TXA2. Kidney levels of angiotensin II were higher in the LS group and significantly increased in the HS group following treatment with LOS alone. However, kidney aldosterone levels were significantly reduced in the presence of LOS in the HS group. Total cholesterol, LDL cholesterol, and triglycerides were significantly higher in the LR group. Together, these data suggest a contribution of endogenous NO and PGs in the antihypertensive effect of LOS and SIM that may be affected by the type of diet.