Objective To investigate the antitumor activity of Fomes Officinalis polysaccharide (FOPS) and the underlying mechanisms. Methods The mice tumor-bearing model was established by subcutaneous injection of S180 ascites tumor cells into the axilla. Mice were randomly divided into control group, model group, CTX group, FOPS-L group, FOPS-M group and FOPS-H group, with 10 mice in each group. The mice were treated with NS, cyclophosphamide or FOPS for 15 d. Tumor inhibition rate and organ index were assessed, and white blood cell ( WBC) and lymphocyte (LYM) were measured. Serum TNF-α, IFN-γ, IL-2, IL-1β and IL-6 were detected by ELISA. The mRNA expression levels of p38MAPK and p-c-jun in tumor tissues were detected by qRT-PCR. The protein expression levels of p38MAPK, p-c-jun, NF-κB and p-NF-κB were detected by Western Blot. Results (1) The mean tumor weights in the CTX and three FOPS groups were significantly decreased compared with the model group (P< 0. 05). The tumor inhibition rate in the CTX and three FOPS groups (-L, -M, -H) were 84. 87%, 54. 29%, 40. 57% and 30. 84%, respectively. (2) Compared with the model group, the spleen index, thymus index, WBC and LYM were increased significantly in the FOPS-L groups (P< 0. 05). (3) Compared with the model group, the levels of TNF-α, IFN-γ, IL-2 in the FOPS-L group were significantly increased (P< 0. 05), while the levels of IL-1β and IL-6 in the CTX and three FOPS groups were significantly decreased (P< 0. 01). (4) The mRNA expression levels of p38MAPK and p-c-jun, and the protein expression levels of p38MAPK, p-c-jun and p-NF-κB in tumor tissue were significantly increased compared with the model group (P< 0.05). Conclusions FOPS has significant anti-tumor activities, and the mechanism of action is related to activation of the MAPK/ NF-κB signaling pathway.