Areca-nut chewing has been well established as a major risk factor for oral cancer and precancerous diseases, whose pathophysiology has been associated with immune deterioration. Previous studies reported that areca nut extracts (ANE) affected the functionality of lymphocytes and neutrophils in vitro. We recently showed that intraperitoneal administration of ANE modulated antigen-specific immunity and promoted inflammatory reactions in ovalbumin (OVA)-sensitized mice. The objective of the present studies was to further investigate the in vivo effect of ANE on T cell-mediated immune responses. In non-sensitized mice, a single oral dose of ANE (200 mg/kg) markedly suppressed the production of interferon (IFN)-γ by splenocytes stimulated with the T cell mitogen concanavalin A, whereas the expression of interleukin (IL)-2 or IL-4 was unaltered. In OVA-sensitized mice, daily administration of ANE (200 mg/kg) for 9 days significantly suppressed the antigen-induced production of IFN-g by splenocytes and the serum level of antigen-specific IgM. Both the cellularity and the metabolic activity of splenocytes were unaffected by the ANE treatment. Collectively, these results demonstrated that oral administration of ANE modulated antigen-specific T cell responses. As IFN-g is a key cytokine involved in the activation of various immunocompetent cells, ANE-mediated suppression of IFN-γ production may be a critical mechanism contributing to the immune deterioration associated with areca-related oral diseases.