The mechanism of action of thalidomide in the treatment of patients with Behçet's disease (BD) is poorly understood. There is some evidence to suggest that certain immunological abnormalities are associated with the pathogenesis of BD. A BD-like mouse model induced by herpes simplex virus (HSV) inoculation shows similar immunological abnormalities. In this study, thalidomide was administered in order to understand the mechanism for the improvement in symptoms in BD-like mice. Eight out of ten thalidomide-treated mice showed improvement but none of ten placebo-treated mice (P < 0.005). The improvements were seen in mucocutaneous symptoms. The mice were sacrificed on the 6th day, and the spleens subjected to RT-PCR, FACS, Western blot and immunohistochemical analysis. IL-2, IL-4, IL-6, IL-10, IFN-gamma, TNFalpha, TGFbeta, MCP-1, RANTES, perforin, IP-10, FasL, FasR and MIP-lalpha were determined. Among these, TNFalpha, MIP-1alpha, perforin and Fas were influenced by thalidomide treatment. These results suggest that thalidomide can attenuate HSV-induced BD-like symptoms in mice through the downregulation of TNFalpha (P < 0.005) and the upregulation of MIP-1alpha (P < 0.005), perforin (P < 0.05) and FasR (P < 0.1).