Several clinical features are consistent with nervous system involvement in the pathogenesis of rheumatoid arthritis. The neuropeptide substance P is one possible mediator of this interaction, since it can be released into joint tissues from primary sensory nerve fibers. The potential effects of the peptide on rheumatoid synoviocytes were examined. The results show that substance P stimulates prostaglandin E₂ and collagenase release from synoviocytes. Furthermore, synoviocyte proliferation was increased in the presence of the neuropeptide. Similar effects were observed with a truncated form of substance P. Synoviocytes were sensitive to very small doses of the neuropeptide (10^-9M), and its effects were inhibited by a specific antagonist. Thus, the specific stimulation of synoviocytes by the neuropeptide substance P represents a pathway by which the nervous system might be directly involved in the pathogenesis of rheumatoid arthritis.