Individuals affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. Stimulation of the hypothalamic melanocortin 4 receptor (MC4-R) produces relative anorexia and increased metabolic rate, even in a relatively starved state. Here we demonstrate that cachexia induced by lipopolysaccharide administration and by tumor growth is ameliorated by central MC4-R blockade. MC4-R knock-out mice or mice administered the MC3-R/MC4-R antagonist, agouti-related peptide, resist tumor-induced loss of lean body mass, and maintain normal circadian activity patterns during tumor growth. The final tumor mass is not affected in these animals,providing further support for the potential role of MC4-R antagonism in the treatment of cachexia in disease states.