Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects multiple synovial joints. Proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)alpha play important roles as principle inflammatory and destructive components of the disease. RA is known to be associated with significant gender differences in its prevalence and clinical features. We found that a potent androgen, 5alpha-dihydrotestosterone (DHT) inhibits IL-1alpha mRNA expression induced by TNFalpha and the DHT effect was inhibited by an androgen receptor antagonist, hydroxyflutamide (OHF). DHT inhibited the NF-kappaB activation induced by TNFalpha in a manner dependent on the androgen receptor (AR). These results suggest that DHT inhibits the TNFalpha-induced IL-1alpha mRNA expression by inhibiting NF-kappaB activation, and contributes to the gender differences of the disease.