Arginase and nitric oxide synthase (NOS) compete for the same substrate, L-arginine. The reciprocal regulation of arginase and NOS in L-arginine-metabolizing pathways has recently been demonstrated. Since NOS is involved in the inflammation of human arthritides, we hypothesized that this reciprocal regulation might also occur within the inflamed synovium. The present study shows that both serum arginase activity and protein levels were significantly higher in patients with rheumatoid arthritis (RA) than in patients with systemic lupus erythematosus (SLE) or osteoarthritis (OA) or in healthy controls. Arginase protein concentrations in supernatants of monocyte cultures from RA patients were also significantly higher than in those from SLE or OA patients or healthy controls. In RA patients, there was a significant correlation between the serum concentrations of arginase protein and rheumatoid factor (r= 0.82, p< 0.0001). These data indicate that increased arginase production is seen in RA patients, but not in other immune-related diseases, suggesting that increased arginase production is unique to, and may play an important role in, the pathogenesis of RA disease.