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OBJECTIVE: The aim of this work was to explore whether lncRNA-MEG3 could serve as a serum biomarker for diagnosing chronic hepatitis B (CHB) and improve the early diagnostic and treatment efficacies. PATIENTS AND METHODS: Serum level of lncRNA-MEG3 in CHB patients and healthy controls was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Subsequently, CHB patients were divided into HBeAg-positive group and HBeAg-negative group based on the infection condition of hepatitis B virus. Correlation analyses were conducted to investigate the relationship between lncRNA-MEG3 level and HBV. Correlation between serum level of lncRNA-MEG3 and liver fibrosis was also analyzed. Survival analyses were performed to elucidate whether lncRNA-MEG3 could be served as a serum biomarker for diagnosing CHB combined with liver fibrosis. Expression levels of lncRNA-MEG3, α-SMA, and COL1A1 in mouse hepatic stellate cells (HSCs) were detected. RESULTS: Serum level of lncRNA-MEG3 was lower in CHB patients compared with that of healthy controls, which was negatively correlated to liver fibrotic degree. Survival analyses showed that serum level of lncRNA-MEG3 exerts significant diagnostic value on the liver fibrotic degree in CHB patients. ROC (receiver operating curve) results showed the AUC was 0.9395, the sensitivity was 100%, and the specificity was 78.13% in comparing the serum level of lncRNA-MEG3 between CHB patients with liver fibrosis and healthy controls. Further analyses showed that serum level of lncRNA-MEG3 was negatively correlated to levels of α-SMA and COL1A1. However, no significant correlations were found among the serum level of lncRNA-MEG3, HBV, hepatic inflammation and liver function. In vitro experiments showed that lncRNA-MEG3 expression was gradually decreased, whereas expression levels of α-SMA and COL1A1 in HSCs were gradually increased in a time-dependent manner. CONCLUSIONS: Serum level of lncRNA-MEG3 is lowly expressed in CHB patients, which is negatively correlated to the liver fibrotic degree. LncRNA-MEG3 may serve as a diagnostic biomarker for CHB.