Repeated exposure to lipopolysaccharide (LPS) was shown to induce leptin resistance. This study aimed to assess hypothalamic neuroinflammation in animals challenged with repeated injections of LPS. Male C57Bl6 mice were assigned into three different groups according to the following treatments: 7 daily injections of saline (CT); 6 daily injections of saline + 1 injection of LPS on the last day (1LPS, 5ug/animal), or 7 daily injections of LPS (7LPS). After the single injection of LPS, there was a reduction in food intake and body weight. However, after the third injection, the 7LPS animals did not show the hypophagic effect, characterizing the desensitization to the endotoxin. To assess the responsiveness to leptin, control and LPS-treated groups received a leptin injection (5mg/kg, intraperitoneal) and food intake and the expression of p-STAT-3 in the hypothalamus were determined. Leptin injection reduced food intake and increased STAT3 phosphorylation in the control group, but not in the 7LPS group. Exogenous leptin did not present an additional effect on the 1LPS-induced hypophagia. We also observed that the expression of SOCS3, PTP1B, and TCPTP, leptin signaling counter-regulators, were increased in the 7LPS group compared to the control, but not in the 1LPS group. Furthermore, we observed neuroinflammation characterized by morphological microglial changes in both acute and repeated exposure to LPS, compared to the control group. These data indicate that repeated exposure to LPS leads to neuroinflammation, and expression of leptin counteracting proteins that ultimately contribute to leptin resistance in the hypothalamus.