BACKGROUND: OLEUROPEIN is a natural antioxidant and scavenging free radicals. In the present study, we examined effect of OLEUROPEIN on paraoxonase 1 (PON1) activity, lipid peroxidation, lipid profile, atherogenic indices, and relationship of PON1 activity by high-density lipoprotein cholesterol (HDL-C) and atherogenic indices in gentamicin (GM) -induced nephrotoxicity in rats.METHODS: This is a lab trial study in Khorramabad, Lorestan province of Iran (2013). Thirty Sprague-Dawley rats were divided into three groups to receive saline; GM, 100 mg/kg/d; and GM plus OLEUROPEIN by 15 mg/kg i.p daily, respectively. After 12 days, animals were anaesthetized, blood samples were also collected before killing to measure the levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL), HDL-C, atherogenic index, lipid peroxidation and the activities of PON1 of all groups were analyzed. Data were analyzed, and P<0.050 was considered significant.RESULTS: OLEUROPEIN significantly decreased lipid peroxidation, TG, TC, LDL, VLDL, atherogenic index, atherogenic coefficient (AC), and cardiac risk ratio (CRR). HDL-C level was significantly increased when treated with OLEUROPEIN. The activity of PON1 in treated animals was (62.64±8.68) that it was significantly higher than untreated animals (47.06±4.10) (P=0.047). The activity of PON1 in the untreated nephrotoxic rats was significantly lower than that of control animals (77.84±9.43) (P=0.030). Furthermore, the activity of PON1 correlated positively with HDL-C and negatively with AC, CRR1, and CRR2 in the treated group with OLEUROPEIN.CONCLUSION: This study showed that OLEUROPEIN improves PON1 activity, lipid profile, and atherogenic index and can probably decrease the risk of cardiovascular death in nephrotoxic patients.