AIM: Piperlongumine (PL), an alkaloid from the Piper longum plant, is acknowledged for various biological properties. The study aimed to explore the protective effect of PL on ischemia reperfusion injury (I/R) in rat kidney. METHODS. 24 adult male Sprague-Dawley rats (200 to 250 mg) were randomly allocated to four groups (n = 6/group): Group I: sham control, Group II: (I/R) renal ischemia/reperfusion kidney renal blocked for 1hour using clamps, followed by 2hr reperfusion. Group III: PL (25 μg/kg) + I/R group and Group IV: PL (50 μg/ kg) + I/R group. Rat kidneys were exposed to 60 min of two-sided deep ischemia followed by 120 min of reperfusion. PL (25 and 50 μg/kg bw) was administered intraperitoneally half an hour before the ischemia. Creatinine, urea, and few renal markers activity in serum were assessed. Oxidative stress and infl ammatory markers were also evaluated. In addition, the expressions of COX-2 and eNOS in animal kidneys were tested by western blotting. RESULTS. Pre-treatment with PL in ischemia-reperfused rats signifi cantly reduced the pathological damage in the kidney and declined the levels of serum creatinine and other renal parameters. PL treatment diminished the serum levels of TNF-α, IL-6, and IL-1β, as well as messenger RNA expressions. Important biological defence parameters such as superoxide dismutase and glutathione levels were upregulated while malondialdehyde levels were down-regulated in PL ischemia rats. CONCLUSION. PL exhibits a protective effect against infl ammation and oxidation in ischemia reperfusion animals (Fig. 5, Ref. 32).