The citrus flavonoid hesperidin has been reported to possess a wide range of pharmacological properties. We have investigated the preventive and therapeutic effects of hesperidin on the development of adjuvant arthritis (AA), a rat model of rheumatoid arthritis (RA). Freund's complete adjuvant was used to induce AA in rats. Secondary paw swelling, polyarthritis index and histopathological assessment of ankle joints were used to evaluate the effects of hesperidin on AA rats. Concanavalin-A-induced T-lymphocyte proliferation and interleukin (IL)-2 production by splenocytes were measured using the MTT assay. Levels of IL-1, IL-6 and tumour necrosis factor (TNF)-alpha secreted by peritoneal macrophages (PM) were measured by RIA. Intragastric administration of hesperidin significantly attenuated secondary paw swelling and reduced the polyarthritis index of AA rats in a dose-dependent manner. In addition, hesperidin clearly ameliorated the pathological changes in AA rats. Hesperidin also restored the suppression of T-lymphocyte proliferation and IL-2 production, and downregulated production of IL-1, IL-6 and TNF-alpha by PM in AA rats. Our results suggest that hesperidin improves AA by downregulating the function of over-active macrophages and by up-regulating the activities of dysfunctional T lymphocytes. Hesperidin may therefore have therapeutic value for the clinical treatment of RA. Further research is required to clarify the detailed mechanisms of the protective effects of hesperidin on AA.