Inflammatory processes contribute to neurodegenerative disease, stroke, encephalitis, and other central nervous system (CNS) disorders. Activated microglia are a source of cytokines and other inflammatory agents within the CNS and it is therefore important to control glial function in order to preserve neural cells. Melanocortin peptides are pro-opiomelanocortin-derived amino acid sequences that include α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH). These peptides have potent and broad anti-inflammatory effects. We tested effects of α-MSH (1-13), α-MSH (11-13), and ACTH (1-24) on production of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) in a cultured murine microglial cell line (N9) stimulated with lipopolysaccharide (LPS) plus interferon γ (IFN-γ). Melanocortin peptides inhibited production of these cytokines and NO in a concentration-related fashion, probably by increasing intracellular cAMP. When stimulated with LPS + IFN-γ, microglia increased release of α-MSH. Production of TNF-α, IL-6, and NO was greater in activated microglia after immunoneutralization of endogenous α-MSH. The results suggest that α-MSH is an autocrine factor in microglia. Because melanocortin peptides inhibit production of proinflammatory mediators by activated microglia they might be useful in treatment of inflammatory/degenerative brain disorders.