Abstract. Introduction: The effect of using high dose pomegranate extract on sepsis and its safety is not clarified. Considering the fact that proper immune and inflammatory responses are needed to cope with infection, the aim of current study was to assess the effect of high dose pomegranate extract consumption on oxidative and inflammatory responses after disease induction in rat model of sepsis. Methods: Sepsis was induced by Cecal Ligation and Perforation (CLP) surgery. Adult male Wistar rats were divided into three groups of eight animals: Sham; CLP and POMx [consumed POMx (250 mg of pomegranate fruit extract/kg/day) for four weeks before CLP]. Results: Peritoneal neutrophil myeloperoxidase activity was significantly lower in POMx compared with Sham and CLP groups (p < 0.01 and p < 0.05, respectively). Although antioxidant enzymes were higher in POMx group after sepsis induction, lower serum total antioxidant status (TAS) (p < 0.01 compared with both CLP and Sham groups) and higher liver thiobarbituric acid reactive species (TBARS) levels were observed in this group (p < 0.01 and p < 0.05, compared with Sham and CLP groups, respectively). Conclusion: High dose POMx consumption prior to sepsis induction, suppressed the vital function of neutrophils in early hours after sepsis initiation, resulting in higher oxidative stress. These findings indicate that caution should be made in using high dose pomegranate products. The main message of current study is that such useful compounds as antioxidants including pomegranate juice which have beneficial effects on general health status may have detrimental effects if misused or used in high doses.