Trichosanthin is an active component extracted from the root tuber of the Chinese medicinal herb Trichosanthes kirilowii. Trichosanthin has abortifacient, anti-tumor, anti-HIV, and immunoregulatory functions. In the current study, we explored its potential effect on allograft rejection in a murine skin transplantation model across a fully mismatched major histocompatibility complex. It was found that treatment of recipient mice with trichosanthin (0.25 or 1 mg/kg, IP) significantly delayed allograft rejection. T cells that originated from recipients treated with trichosanthin were restimulated with donor-specific splenocytes showed a significantly reduced response compared with that of control recipients. In line with these results, the mRNA levels for interleukin (IL)-2 and interferon-gamma were decreased and the levels of IL-4 and IL-10 were increased in splenic T cells originating from trichosanthin-treated recipients. These results indicated that trichosanthin may have potential therapeutic value for transplantation rejection and other inflammatory diseases.