Abstract: Objective: Lentinan (LNT) had been shown to have direct cytotoxicity on cancer cells. However, the mechanism of this anti-tumor effect was still unclear. The purpose of this study was to investigate the effect of lentinan on the proliferation, migration and chemosensitivity of pancreatic cancer cells and its mechanism. Methods: Capan-1 cells from pancreatic cancer were randomly divided into control group, IL-6 group and IL-6+LNT group. Cell survival rate was detected by MTT, expression levels of p-STAT3, STAT3, Notch1 and Hes1 were analyzed by Western blot, and cell migration was observed by Transwell test. The cisplatin resistant cell model (Capan-1/DDP) was established, and the semi-inhibitory concentration of cisplatin (IC₅₀) was detected in each group, and the relative expression levels of Ki67, MMP-9, MRP1 and P-gp were analyzed. Capan-1/DDP cell line was selected for tumor formation test in nude mice to verify the effects of LNT on tumor weight and IL-6/STAT3/Notch signaling pathway in nude mice. Results: Lentinan (7.5~240 µg/mL) could inhibit proliferation of pancreatic cancer cells. Compared with the IL-6 group, the expression levels of p-STAT3/STAT3, Notch1 and Hes1 in IL-6+LNT group were significantly down-regulated, the proliferation rate and the migration level was significantly dcreased (P<0.05, P<0.01). The proliferation rate of Capan-1/DDP cell line, IC₅₀ and the expression levels of Ki-67, MMP-9, MRP1 and P-gp in IL-6+LNT group were significantly down-regulated (P<0.05, P<0.01). In vivo experiments, compared with IL-6 group, the tumor volume and tumor weight in cisplatin+IL-6 group and LNT+IL-6 group was significantly down-regulated, and expression levels of p-STAT3/STAT3, Notch1 and Hes1 were significantly decreased (P<0.05, P<0.01). Conclusion: LNT inhibits proliferation, migration and drug resistance of Capan-1 pancreatic cancer cells, which is related to the regulation of IL-6/STAT3/Notch signal pathway.