Although Radix clematidis has commonly been used in Chinese medicine for the treatment of arthralgia, the anti-diabetic effects of Radix clematidis have not yet been reported. In the present study, we demonstrated that Radix clematidis extract (RCE) could prevent cytokine-induced beta-cell damage and streptozotocin (STZ)-induced diabetes in mice. Treatment of RINm5F insulinoma cells with interleukin-1beta and interferon-gamma reduced cell viability; however, RCE protected the cells from this cytokine-mediated viability reduction in a concentration-dependent manner. Additionally, incubation with RCE resulted in a significant suppression of cytokine-induced nitric oxide (NO) production, which was correlated with reduced levels of the inducible form of NO synthase (iNOS) mRNA and protein. The molecular mechanism by which RCE inhibited iNOS gene expression appeared to involve inhibition of NF-kappaB activation. Furthermore, RCE abolished the cytokine-induced increases in NF-kappaB binding activity and p65 subunit levels in the nucleus, as well as IkappaBalphadegradation in the cytosol when compared to unstimulated cells. The protective effect of RCE was further demonstrated by the observed suppression of NF-kappaB-dependent iNOS expression and normal insulin secreting responses to glucose in cytokines-treated islets. The anti-diabetic effect of RCE was even more striking in vivo, where nearly complete protection against STZ-induced diabetes was observed. Treatment of mice with STZ resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by immunohistochemical staining; however, pretreatment of mice with RCE blocked the destruction of STZ-induced islets and the development of type 1 diabetes.