Background & Aims: The liver is frequently subject to insult because of viral infection, alcohol abuse, or toxic chemical exposure.Extensive research has been conducted to identify blood markers that can better discern liver damage, but little progress has been achieved in clinical practice.Recently, circulating microRNAs (miRNAs) have been reported as potential biomarkers for the noninvasive diagnosis of cancer.Methods & Results: In this study, we investigated whether plasma miRNAs have diagnostic utility in identifying liver disease.The study was divided into 2 phases: marker selection by real-time quantitative PCR analysis of a small set of plasma samples, and marker validation with a large set of plasma samples from patients with chronic hepatitis B viral infections and healthy controls.Two mouse model systems, D-galactosamine-and alcoholinduced liver injury, were also developed to evaluate whether differences in miRNA concentration were associated with various liver diseases.Among the miRNA candidates identified, miR-122 presented a disease severity-dependent change in plasma concentration in the patients and animal models.Compared with an increase in aminotransferase activity in the blood, the change in miR-122 concentration appeared earlier.Furthermore, this change was more specific for liver injury than for other organ damage and was more reliable, because the change was correlated with liver histologic stage.Conclusions: Our findings suggest that circulating miR-122 has potential as a novel, predictive, and reliable blood marker for viral-,alcohol-, and chemicalinduced liver injury.