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Objective: To investigate the tumor suppressing effect of Shenqi Yiliu decoction combined with cisplatin via ERK-mediated C-Myc/PD-L1 phase-coordinated pathway on H22 hepatocellular carcinoma tumor-bearing mice and its mechanism. Methods: In 60 SPF-grade male Kunming mice, 10 mice were taken as blank group by random number table method, and the other 50 mice were replicated as H22 hepatocellular carcinoma tumor-bearing mouse model. After successful replication of the model, the model mice were randomly divided into model group, cisplatin group [2.5x19-3 g/(kg⋅3 d)], Shenqi Yiliu decoction low [13.515 g/(kg⋅d)], medium [27.03 g/(kg⋅d-1) ], and high dose [27.030 g/(kg⋅d)] combined with cisplatin group [2.5x10-3 g/(kg⋅3 d)], 10 mice in each group were treated for 13 d. After 24 h of the last dose, the mice were anesthetized and sacrificed, and the tumor inhibition rate, spleen index and thymus index of each drug group were determined; HE staining was performed to observe the histopathological changes of tumor in mice; ELISA kit was used to detect the contents of EGF and IFN-γ in tumor tissue homogenate; p-ERKl/2, C-Myc and PD-L1 protein expression in tumor tissue were detected by IHC and Western blot; ERK, C-Myc and PD-L1 mRNA expression levels in tumor tissue were detected by RT-PCR. Results: Compared with blank group, the average body mass and spleen index of mice in model group were decreased (P<0.05). Compared with model group, the tumor inhibition effect of each treatment group was obvious, and Shenqi Yiliu decoction combined with cisplatin group inhibited tumor growth in liver cancer mice in a dose-dependent way, improved the average body mass, spleen index and thymus index of mice, promoted the necrosis of tumor cells and increased the necrotic area. EGF and IFN-γ contents, P-ERK1/2, C-Myc, PD-L1 protein expressions and ERK, C-Myc, PD-L1 mRNA expression levels were decreased in tumor tissues (P<0.05). Compared with cisplatin group, the therapeutic effect of Shenqi decoction combined with cisplatin in medium and high dose groups was significant, and the difference was statistically significant (P<0.05). Conclusion: Shenqi Yiliu decoction combined with cisplatin effectively inhibited the tumor growth of H22 liver cancer tumor-bearing mice and significantly reduces the expression of C-Myc and PD-L1 proteins in the tumor tissues, which may be through the regulation of ERK signaling path-way-related protein expression to exert tumor suppressive effect. [ABSTRACT FROM AUTHOR]