Background: Sex difference in eating behavior is well documented. Development of diet-induced obesity in males and females is mediated by distinct mechanisms. Therefore, understanding the key molecular mechanisms involved in the pathogenesis of obesity could be beneficial for the development of a therapeutic approach. Objective:  Assessing whether high fat diet (HFD) induced obesity is sex-specific and the possible effect of pancreatic polypeptide (PYY) and ghrelin on the HFD induced obesity in albino rats. Material and Methods: Sixty four rats of a local strain were divided into 4 equal groups. Each group was divided into male and female subgroups: group I(control group), group II (HFD received rats), group III (HFD- PYY treated rats at a dose of 50 µg⁄ kg twice daily by i.p injection), and group IV( HFD- ghrelin treated rats at a dose of 10 nmol/ day by intraperitoneal injection). Results: There were extensive differences between the sexes in the development of obesity by using high fat diet at the end of 4^th and 5^th weeks. Body weight was significantly lower in females as compared to males. Administration of PYY caused significant decrease in body weight compared to HFD, whereas ghrelin administration caused significant increase in body weight compared to HFD in all groups. Conclusion: Despite extensive similarities in the brain responses to hunger and satiety between male and female, there were sex- differences in the development of obesity and body weight gain. PYY administration reduced HFD induced obesity, while a ghrelin administration exaggerated the degree of obesity.