The ability of amylin to reduce acute food intake in rodents is well established. Longer-term administration in rats (up to 24 d) shows a concomitant reduction in body weight, suggesting energy intake plays a significant role in mediating amylin-induced weight loss. The current set of experiments further explores the long-term effects of amylin (4-11 weeks) on food preference, energy expenditure, and body weight and composition. Furthermore, we describe the acute effect of amylin on locomotor activity and kaolin consumption to test for possible nonhomeostatic mechanisms that could affect food intake. Four wk subcutaneous amylin infusion of high fat-fed rats (3-300 µg/kg/d) dose-dependently reduced food intake and body weight gain (ED₅₀ for body weight gain=16.5 µg/kg/d). The effect of amylin on body weight gain was durable for up to 11 wks, and associated with a specific loss of fat mass and increased metabolic rate. The body weightof rats withdrawn from amylin (100 µg/kg/d) after 4 wks of infusion returned to control levels 2 wks after treatment cessation, but did not rebound above control levels. When self-selecting calories from a low or high fat diet during 11 wks of infusion, amylin-treated rats (300 µg/kg/d) consistently chose a larger percentage of calories from the low fat diet versus controls. Amylin acutely had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. These results demonstrate pharmacological actions of amylin in long-term body weight regulation, in part through appetitive-related mechanisms, and possibly via changes in food preference and energy expenditure.