To compare the anorectic effectiveness of leptin and the amylin analogue salmon calcitonin (sCT), rodents were treated on 1 day with subcutaneous injections. In chow-fed C57Bl/6J mice, leptin and sCT reduced energy intake and acted additively. After C57Bl/6J mice had become leptin-resistant on being fed chocolate as a palatable high-caloric supplement to chow, their sCT-induced decrease in energy intake was more pronounced than in chow-fed mice with differential changes in the intake of chocolate (strong reduction) and chow (slight increase). Dose-response relationships for sCT-induced reductions in energy intake were analysed in chow-fed C57Bl/6J mice and two obese strains, ob/ob mice and melanocortin-4 receptor knockout (MC4-r-KO) mice, as well as in wild-type and fatty (fa/fa) rats. Compared to C57Bl/6J mice, reduction in food intake induced by sCT was attenuated in MC4-r-KO mice, and nearly absent in ob/ob mice, over the dose range investigated. Compared to C57Bl/6J mice, wild-type rats responded more sensitively to sCT and its efficiency was only slightly reduced in fatty (fa/fa) rats. Thus, while genetically induced failures of leptin signalling reduce the action of sCT, it effectively inhibits the intake of a palatable, high fat-high sugar diet even in states of diet-induced obesity with functional leptin resistance.