We have generated three fully human monoclonal antibody antagonists against fibroblast growth receptor-1 (FGFR1) that potently block FGF-signaling. We found that antibodies targeting the c-splice form of the receptor (FGFR1c) were anorexigenic when administered intraperitoneally (i.p.) 3 times weekly to mice, resulting in rapid, dose-dependent weight loss that plateaued (for doses greater than 4 mg/kg) at 35-40% in 2 weeks. Animals appeared healthy during treatment and regained their normal body weights and growth trajectories upon clearance of the antibody from the bloodstream. Measurements of food consumption and energy expenditure indicated that the rapid weight loss was induced primarily by decreased energy intake and not by increased energy expenditure or cachexia, and was accompanied by a greater reduction in fat than lean body mass. Hypophagia was not caused through malaise or illness as indicated by absence of conditioned taste aversion, pica behavior, and decreased need-induced salt intake in rats. In support of a hypothalamic site of action, we found that after i.p. injections, anti-FGFR1c (IMC-A1), but not a control antibody, accumulated in the median eminence and adjacent mediobasal hypothalamus, and that the FGFR1c splice form is enriched in the hypothalamus of mice. Furthermore, a single intracerebroventricular administration of 3 µg IMC-A1 via the 3rd-ventricle to mice caused ~36% reduction in food intake and 6% weight loss within the ensuing 24 hours. Our data suggest that FGF-signaling through FGFR1c may play a physiological role in hypothalamic feeding circuit, and that blocking it leads to hypophagia and weight loss.