Cobalt protoporphyrin (CoPP) in single subcutaneous doses produces prolonged weight loss in adult and aged male rats. The altered body weight level in treated animals is actively defended against starvation or overfeeding over prolonged time periods (greater than 50-100 days). The actions of CoPP on appetite and body weight regulation are biphasic, comprising an initial period of hypophagia, probably mediated centrally, until a particular body weight level is attained. Resumption of normal calorie intake follows, although lowered body weight levels are sustained, suggesting an additional action of the compound on peripheral substrate metabolism. Controlled decrements in body weight can be produced by repetitive low-dose CoPP treatment (e.g., 1 mumol/kg body wt weekly); low-dose regimens do not elicit altered hormonal homeostasis or aberrations in heme/cytochrome P-450 regulation that have been observed following larger doses (25-50 mumol/kg body wt) of the compound. CoPP may be a valuable probe with which to explore the role of heme-related molecules in the regulation of appetite and body weight.