OBJECTIVE: To explore the action mechanisms of Huangqi Decoction Granules (, HQDG) on hepatitis B cirrhosis. METHODS: A total of 85 patients with hepatitis B cirrhosis were randomly divided into HQDG group (42 cases) and control group (43 cases) by a random number table and were treated with HQDG or placebo for 48 weeks (6 g per times and orally for 3 times a day), respectively. After RNA-sequencing of serum samples extracted from the patients, the differentially expressed genes (DEGs) in HQDG and control groups before and after treatment were separately screened. The DEGs were then performed pathway enrichment analysis and proteinprotein interaction (PPI) network analysis. The expression levels of key genes were detected by quantitative realtime polymerase chain reaction (qRT-PCR). RESULTS: After the investigation, 4 and 3 cases were respectively excluded from HQD and control groups because of the incomplete data. Additionally, 3 and 5 cases were lost to follow up in HQD and control groups respectively. Finally, a total of 70 cases with good compliance were included for further DEGs analysis. A total of 1,070 DEGs (including 455 up-regulated genes and 615 down-regulated genes) in HQDG group and 227 DEGs (including 164 up-regulated genes and 63 down-regulated genes) in the control group were identified after treatment. Compared with the control group, 1,043 DEGs were specific in HQDG group. Besides, 1 up-regulated transcription factor (TF, such as GLI family zinc finger 1, GLI1) and 25 down-regulated TFs (such as drosophila mothers against decapentaplegic proteinfamily member 2, SMAD2) were identified. Pathway enrichment analysis showed that down-regulated Ras homolog gene family member A (RHOA) was enriched in pathogenic Escherichia coli infection. In the PPI network, up-regulated epidermal growth factor receptor (EGFR), and down-regulated cell division cycle 42 (CDC42) as well as v-akt murine thymoma viral oncogene homolog 1 (AKT1) had higher degrees. Moreover, long non-coding RNAs (lncRNA) growth arrest-specific 5 (GAS5) was involved in the lncRNA-target regulatory network. Furthermore, qRT-PCR revealed that expression levels of CDC42 and GLI1 had significant differences in HQDG group before and after treatment (P<0.05). CONCLUSIONS CDC42 and GLI1 may be the targets of HQDG in patients with hepatitis B cirrhosis. Additionally, SMAD2, EGFR, AKT1, RHOA and GAS5 might be associated with the curative effect of HQDG on hepatitis B cirrhosis patients.