Aim of this study: To confirm the anti-arthritic effect and explore the potential mechanism of the dried heartwood of Caesalpinia sappan L (HCS) on collagen-induced arthritis (CIA) in rats, an animal model of rheumatoid arthritis. Materials and methods: CIA was induced in male Wistar rats by intradermal injection of bovine collagen-II in Freund's incomplete adjuvant (IFA). The rats in the onset of arthritis were treated daily with oral administration of an ethanol extract from HCS (EHCS) at different doses (1.2, 2.4 and 3.6 g/kg) or olive oil-vehicle for 10 days. Paw swelling, arthritis index, radiographic and histopathologic changes were evaluated to confirm the anti-arthritic effect of EHCS on CIA in rats. Levels of proinflammatory cytokines interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) as well as prostaglandin E2 (PGE2) in blood and expression of cyclooxygenase-2 (COX-2) and transcription factor NF-kappa B p65 in paw cartilage were detected to further study the molecular mechanism of the anti-arthritic effects of EHCS on CIA in rats. In addition, the adverse effects of EHCS on liver and kidney of rats were also evaluated. Results: The results showed that the EHCS markedly attenuated collagen-induced arthritis and reduced the levels of IL-1 beta, IL-6, TNF-alpha and PGE2 in serum and the expression of COX-2 and transcription factor NF-kappa B p65 in paw cartilage of CIA rats. EHCS (3.6 g/kg) induced slight hepatotoxicity and body weight loss. Conclusion: These results indicate that EHCS significantly attenuates CIA in rats by decreasing the levels of IL-1 beta, IL-6, TNF-alpha and PGE2 in serum and the expression of COX-2 and transcription factor NF-kappa B in paw cartilage. (C) 2011 Elsevier Ireland Ltd. All rights reserved.