Hepatitis B cirrhosis is caused by liver cell necrosis, residual liver cell nodular regeneration, connective tissue hyperplasia and fiber formation, which frequently leads to adrenal insufficiency. Previous reports have demonstrated that human fibroblast growth factor (hFGF)-21 is a multifunctional protein that exhibits potential therapeutic value for metabolic diseases. The present study investigated the diagnostic value of hFGF-21 and analyzed the potential molecular mechanism in the progression of hepatitis B cirrhosis combined with adrenal insufficiency. Characteristics of cellular immunity and humoral immunity were analyzed in patients with hepatitis B cirrhosis combined with adrenal insufficiency (PhbA). Results demonstrated that expression levels of hFGF-21 were downregulated in plasma and liver cells isolated from clinical specimens. Plasma concentration levels of hFGF-21 were upregulated in prognostic PhbA. In vitro assays indicated that hFGF-21 treatment decreased the continuous deposition of extracellular matrix and reactive oxygen species in liver cells isolated from clinical specimens. Results also demonstrated that hFGF-21 treatment downregulated inflammatory cytokines. It was observed that hFGF-21 treatment downregulated nuclear factor (NF)-κB and Kruppel-like factor 6. Notably, transforming growth factor (TGF)-β, platelet-derived growth factor and epidermal growth factor levels were improved by hFGF-21 treatment. In conclusion, these results indicated that hFGF-21 inhibits inflammation by regulation of the NF-κB-mediated TGF-β signaling pathway, which may serve as a predictor and prognostic factor in PhbA.Keywords: adrenal insufficiency; hepatitis B cirrhosis; human fibroblast growth factor-21; inflammation; nuclear factor-κB; transforming growth factor-β.