Entamoeba histolytica is a protozoan parasite that causes amebic colitis, an invasive disease responsible for as many as 100,000 deaths per year globally. Leptin signaling protects from amebiasis, with query molecular mechanism. This study aimed to evaluate the effect of leptin Receptor Q223R Polymorphism on Egyptian children with Entamoeba histolytica infection. After ethical clearance, blood and fecal samples were taken from one hundred children with E. histolytica and 100 children as control group. All children were subjected to anthropometric assessment. Entamoeba infected group was further assessed for severity of symptoms, cyst load, and ELISA for differentiation of E. histolytica from E. dispar. Q223R LEPR polymorphism then performed for both groups. RR was higher in children with E. histolytica group while QQ and QR were higher in control group. Heavy cyst count, severe underweight, severe symptoms, and median leptin level was higher in RR group compared to QQ & QR groups. The highest risk of R allele was severe underweight, severe symptoms and high leptin level.