Circulating levels of the pancreatic -cell peptide hormone amylin and the gut peptide PYY[3–36] increase following nutrient ingestion. Both have been implicated as short-term signals of meal termination with anorexigenic and weight-reducing effects. However, their combined effects are unknown. We report that the combination of amylin and PYY[3–36] elicited greater anorexigenic and weight-reducing effects than either peptide alone. In high-fat fed rats, a single intraperitoneal injection of amylin (100 µg/kg) + PYY[3–36] (1000 µg/kg) reduced food intake for 24 hours (P < 0.05 vs. vehicle), while the anorexigenic effects of either PYY[3–36] or amylin alone diminished after 6 hours post-injection. These anorexigenic effects were dissociable from changes in locomotor activity. Subcutaneous infusion of amylin + PYY[3–36] for 14 days suppressed food intake and body weight to a greater extent than either agent alone in both rat and mouse DIO models (P < 0.05). In DIO-prone rats, 24-hour metabolic rate was maintained despite weight loss, and amylin + PYY[3–36] (but not monotherapy) increased 24-hour fat oxidation (P < 0.05 vs. vehicle). Finally, a 4*3 factorial design was used to formally describe the interaction between amylin and PYY[3–36]. DIO-prone rats were treated with amylin (0, 4, 20, 100 µg/kg·d) and PYY[3–36] (0, 200, 400 µg/kg·d) alone and in combination for 14 days. Statistical analyses revealed that food intake suppression with amylin + PYY[3–36] treatment was synergistic, while body weight reduction was additive. Collectively, these observations highlight the importance of studying peptide hormones in combination, and suggest that integrated neurohormonal approaches may hold promise as treatments for obesity.