The aim of this study was to determine if the anticytokine neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) occurs, along with interleukin 1 receptor antagonist (IL-1ra) and soluble tumor necrosis factor receptor (sTNFr), in synovial fluid of patients with rheumatoid arthritis (RA), juvenile chronic arthritis (JCA), or osteoarthritis. The data show that alpha-MSH does occur in the synovial fluid and its concentrations are greater in patients with RA than in those with osteoarthritis. Synovial fluid concentrations of IL-1ra and sTNFr were likewise greater in RA. Further, concentrations of alpha-MSH, IL-1-ra, and sTNFr were greater in patients with polyarticular/systemic-onset JCA than in those with pauciarticular disease, that is in patients with greater joint inflammation. Concentrations of alpha-MSH were greater in synovial fluid than in plasma in a substantial proportion of patients, suggesting local production of the peptide; this is the first indication that the anticytokine molecule alpha-MSH is produced within a site of inflammation. Further, it appears that local production of alpha-MSH is induced particularly in those arthritic joints that have more intense inflammatory reactions. This finding, combined with previous evidence of the marked anti-inflammatory activity of alpha-MSH, suggests that the peptide acts locally to modulate proinflammatory influences in rheumatic diseases.