Objective: To investigate of Lactarius deliciosus gray polysaccharide (LDG-A) therapeutic effect on primary hepatocellular carcinoma and to analyze its mechanism. Methods: When the human hepatocarcinoma cells HepG2 was cultured to the logarithmic phase, 1.5×10⁶/well were subdivided into 6-well plates. The cells were randomly divided into 4 groups. Each group had 5 replicate wells. After adherent growth, the blank group, experiment 1, 2, 3 groups were treated with phosphate buffered saline (PBS), 50, 150, and 300 μg/mL LDG-A, respectively. The rates of proliferation inhibition and apoptosis of the cells after 24, 48, and 72 hours of intervention were compared. The mRNA and protein relative expression of proliferation-related genes vascular endothelial growth factor (VEGF), phosphatidylinositol 3-kinase (PI3K), hepatocyte adhesion molecule 1 (hepaCAM1) and apoptosis-related genes B lymphoma-2 gene (Bcl-2), Bcl-2 associated X protein (Bax), cleaved cysteinyl aspartate specific proteinase-3 (cleaved-caspase-3), after 72 hours intervention were compared. Results: The proliferation inhibition rate of the experiment 2 group was the highest, the experiment 3 group was the second, the experiment 1 group was the lowest, and there were significant differences between each 2 groups (P<0.05). The apoptosis rate of the experiment 2 group was the highest, the experiment 3 group was the second, the experiment 1 group was slightly lower, the control group was the lowest, and there were significant differences between each 2 groups (P<0.05). The proliferation inhibition rates and the apoptosis rates of the 3 experiment groups were significantly increased with time (P<0.05). The apoptosis rate of the control group did not change significantly with time (P>0.05). The mRNA and protein relative expressions of VEGF, PI3K and Bcl-2 of the experiment 2 group were the lowest, the experiment 3 group was the second, the experiment 1 group was slightly higher, the blank group was the highest, and there were significant differences between each 2 groups (P<0.05). The mRNA and protein relative expressions of hepaCAM1, cleaved-caspase-3 and Bax of the experiment 2 group were the highest, the experiment 3 group was the second, the experiment 1 group was slightly lower, the blank group was the lowest, and there were significant differences between each 2 groups (P<0.05). Conclusion: LDG-A can inhibit the proliferation of human hepatocarcinoma cells HepG2 and promote its apoptosis, of which 150 μg/mL LDG-A best, and it is presumed to be related to down-regulate the mRNA and protein expressions of VEGF, PI3K, Bcl-2 and up-regulate the mRNA and protein expressions of hepaCAM1, cleaved-caspase-3 and Bax.