This study was designed to evaluate the effects of oral administration of a water extract made from the Rhizoma Atractylodis Macrocephalae (RAM) on the immune responses in mice immunized with FMDV type O vaccine. Thirty-five ICR mice were randomly divided into five groups with seven animals in each group, and orally administered daily for 4 days at a dose equivalent to 0, 0.0625, 0.125, 0.25 or 0.5 g of dried RAM, respectively. After that, the animals were subcutaneously immunized twice with FMDV vaccine at 2-week intervals. Blood samples were collected 3 weeks after boosting for measurement of FMDV-specific IgG titers and the IgG subclasses, lymphocyte proliferation as well as production IL-5 and IFN-gamma. Results indicated that serum FMDV-specific IgG titers and the IgG subclass responses were significantly enhanced in mice orally administered RAM at the dose of 0.25 or 0.5 g when compared with the control group (P<0.05). Splenocyte proliferation in response to Con A and LPS and production of IL-5 and IFN-gamma by splenocytes were also significantly enhanced (P<0.05). Considering the immunomodulatory effect and safety of RAM demonstrated in this study, this herb deserves further investigation to evaluate its potential improvement of FMD vaccination in other animals such as pigs, goats and cattle.