Previous studies suggest that down-regulation of the major histocompatibility complex (MHC) antigens on the cell surface of certain tumors results in an escape of immune surveillance. Cordyceps sinensis is well known for its modulatory effect on host immune system. To investigate the modulatory effect of Cordyceps sinensis on MHC class II antigen expression on hepatoma cells, immunostaining with monoclonal antibody (MAb) L243, against the HLA DR region of MHC class II antigens on human hepatoma cell line HA22T/VGH was analyzed by using flow cytofluorimetry. The degree of fluorescence intensity on L243 (+) cells was expressed as relative mean fluorescence intensity (RMFI). The extract of Cordyceps sinensis (VGH-CS-ME-82, 40 μg/ml) was found to increase the MHC class II antigen expression on HA22T/VGH cells with the percentage of L243 (+) cells 40.2 ± 2.5 and RMFI 6.6 ± 0.4; whereas cells without treatment disclosed the percentage of L243 (+) cells 17.2 ± 1.4 and RMFI 5.4 ± 0.3, respectively (p < 0.05). There was a dose-related increase in the degree of fluorescence intensity in terms of RMFI on VGH-CS-ME-82 induced cells. The RMFI in cells treated with IFN-γ0, 0.2 and 5 ng/ml were 5.4 ± 03, 8.2 ± 0.4, and 24.9 ± 1.5, respectively; whereas the RMFI in cells co-incubated with VGH-CS-ME-82 (40 μg/ml) and IFN-γ0, 0.2 ng/:ml and 5 ng/ml were 6.7 ± 0.2 (p <0.05), 9.2 ± 0.9 (p < 0.1) and 29.5 ± 1.2 (p < 0.005), respectively. We conclude that VGH-CS-ME-82, either alone or with IFN-γ induction, increases the MHC class II antigen expression on hepatoma cell line HA22T/VGH, which will shed light into the present immunotherapy, and make the host immune surveillance more effective against tumor cells with down-regulated MHC class II antigen expression.