Undernutrition increases susceptibility to diarrheal diseases. The adipocytokine leptin imparts protection from amebiasis. We tested the role of leptin signaling in cellular resistance to E. histolytica cytotoxicity in HEK cells transfected to express the leptin receptor. Protection from amebic killing was conferred by the leptin receptor. It required activation of the transcriptional regulator STAT3 by the leptin receptor, as mutation of the STAT3 activation domain of the receptor, or addition of a STAT3 small-molecule inhibitor, reversed protection. In contrast, a leptin receptor containing a common polymorphism (Q223R) known to increase susceptibility to amebiasis in humans provided significantly less protection. Consistent with the importance of STAT3, the Q223R polymorphism decreased l leptin-dependent STAT3 activation by 21% relative to the WT receptor (P=0.035). Microarray analysis identified potential downstream effectors of STAT3-mediated protection, most importantly TRIB1 and SOCS3, which appear to having opposing roles in the regulation of E. histolytica induced apoptosis. Together these data demonstrated that leptin increased the resistance of host cells to E. histolytica cytotoxicity via a STAT3-dependent mechanism. Additionally we found that the Q223R polymorphism in the leptin receptor, known to increase susceptibility to E. histolytica infection, decreased STAT3 activation and decreased host resistance to amebic cytotoxicity. This is the first demonstration of a host-signaling pathway that restricts amebic pathogenesis. Additionally, this finding represents an important advance in our mechanistic understanding of the role of leptin in the relationship between undernutrition and increased susceptibility to infection.