Background: Liver cirrhosis results from many forms of chronic damage, characterized by accumulation of extracellular matrix. The present study aimed to explore a potential non-invasive biomarker and its mechanism in the progression of liver cirrhosis.Methods: Gene Expression Omnibus (GEO) dataset (GSE15654, n = 216) was analyzed to screen genes associated with progression of liver cirrhosis. A total of 181 plasma samples, including healthy control (HC, n = 20), chronic hepatitis B (CHB, n = 77) and HBV-related liver cirrhosis (LC, n = 84), were enrolled for validation. In vitro and in vivo experiments were employed for the mechanistic investigation. Results: GEO dataset analysis showed that relatively low mRNA-expression of C –C motif chemokine ligand 16 (CCL16) was associated with elevated Child-Pugh score ( P = 0.034) and worse prognosis ( P = 0.025). Plasma CCL16 level decreased in a stepwise patt, with a median concentration of 10.29, 6.57 and 4.47 ng/mL in the HC, CHB and LC groups, respectively ( P < 0.001). Low plasma CCL16 was significantly related to hepatic dysfunction both in the CHB and LC groups ( P < 0.05). Combination of CCL16 and ALT showed improved distinguishing capability for LC compared to either alone. In vitro , CCL16 expression was downregulated by lipopolysaccharide and hypoxia. Overexpression of CCL16 from human normal liver cell line (LO2) reduced the extracellular matrix associated proteins (Col1 and Col4) in human hepatic stellate cell line (LX-2). In vivo , the pathological feature of cirrhosis was alleviated by the hepatocyte- specific expression of CCL16. Conclusions: CCL16 could be a feasible plasma marker to predict the occurrence and progression of liver cirrhosis. CCL16 might impact liver cirrhosis through inactivating hepatic stellate cells.