Interleukin-1β (IL-1β) mediates many of the behavioral responses to infection and inflammation, and IL-1β-converting enzyme (ICE) processes intracellular IL-1β, leading to its maturation and secretion. Here we demonstrate that intracerebroventricular injections of lipopolysaccharide (LPS) produced a greater reduction in both food intake and food-motivated behavior in wild-type compared with ICE-deficient (ICE −/−) mice. This defect occurred although ICE −/− mice were able to fully respond to intracerebroventricular injections of IL-1β. In contrast, ICE −/− mice remained fully responsive to intraperitoneal injections of LPS. These results indicate that brain, but not peripheral, IL-1β plays a critical role in the depression in food intake that occurs during inflammation.