Objective To investigate the anti-tumor effects and mechanism of Pleurotus geesteranus powder (PGP) on H22 tumor-bearing mice. Methods The mouse tumor-bearing model was established by subcutaneous injection of ascites of H22 hepatocellular carcinoma into mice via the axilla. Sixty male ICR mice were randomly divided into one blank control (C) and five H22 tumor-bearing groups including tumor model control, positive control (cyclophosphamide, CTX) and three PGP groups. The mice in the model control group received 0. 9% saline solution by oral gavage, the mice in the positive control group were intra-abdominally injected with CTX saline solution (20 mg / kg body weight every other day), and mice in the PGP-treated groups were administered PGP (dispersed in 0. 9% saline solution) at low (750 mg / kg body weight, PGP-L), mid (1500 mg / kg body weight, PGP-M) and high (3000 mg / kg body weight, PGP-H) doses per day. The administration cycle was 10 d. When the trial was finished, the mean tumor weight, tumor inhibition rate and immune organ index were calculated, and the levels of serum immunoglobulins and cytokines, and antioxidant parameters in the liver and kidney were determined. Microscopic morphology of tumor and spleen tissues were observed by hematoxylin and eosin ( HE) staining. Results ( 1) The mean tumor weight in the CTX and three PGP groups was significantly decreased compared with the model control (P< 0. 01). The tumor inhibition rate in the CTX and three PGP groups (low, mid, high) were 55. 18%, 29. 06%, 47. 47%, and 48. 80%, respectively. ( 2) Compared with the blank control, the spleen index (P < 0. 01), levels of serum immunoglobulin A (IgA, P< 0. 01) and tumor necrosis factor α (TNF-α, P< 0. 05), and liver malondialdehyde (MDA, P< 0. 05) were increased in the model group, whereas serum interleukiN-2 (IL-2) content (P< 0. 01), activities of liver catalase (CAT, P< 0. 01), glutathione peroxidase (GSH-Px, P< 0. 01), kidney superoxide dismutase (SOD, P< 0. 01), GSH-Px (P< 0. 05), and CAT (P< 0. 01) in the model group were significantly decreased. Furthermore, the serum IL-6 content in the model group tended to be increased (P > 0. 05). The thymus index in the CTX group was significantly higher than in the blank control (P< 0. 05). (3) Treatment with PGP reversed the above abnormal performance in the model control. Levels of IgA and TNF-α in the three PGP treated ( low, mid, high) groups (IgA: P < 0. 01, P < 0. 01, P < 0. 01; TNFα: P < 0. 05, P < 0. 01, P < 0. 05), IL-6 levels in the PGP-H group (P< 0. 05), and liver MDA content in the PGP-M group (P<0. 05) were lower than in the model control group. IL-2 levels in the PGP-L group (P<0. 05), activities of liver CAT (P< 0. 05, P< 0. 05, P< 0. 01), kidney CAT (P< 0. 01, P< 0. 01, P< 0. 01) and kidney SOD (P< 0. 01, P< 0. 01, P< 0. 01) in three PGP-treated ( low, mid, high) groups, liver GSH-Px in the PGP-M and PGP-H groups (P< 0. 05), and kidney GSH-Px in the PGP-L and PGP-M groups (P< 0. 01) were significantly higher than in the model control group. ( 4) Compared with the CTX group, the spleen index in the PGP-H group was increased, and IL-6 levels were decreased significantly ( P < 0. 05 ). ( 5 ) Furthermore, compared with the model control group, increased necrotic areas of tumors in the CTX group and all PGP groups were observed by HE staining. Conclusions PGP might have anti-tumor effects related to its immunoregulatory and antioxidant functions.