MicroRNAs are fine tuners of diverse biological responses and are expressed in various cell types of the liver. Here we hypothesized that circulating microRNAs (miRNAs) may serve as biomarkers of liver damage and inflammation. We studied miRNA‐122, which is abundant in hepatocytes, and miR‐155, ‐146a, and ‐125b, which regulate inflammation in immune cells in mouse models of alcoholic liver disease (ALD), drug (acetaminophen, APAP)‐induced liver injury (DILI), and Toll‐like receptor (TLR) 9+4 ligand‐induced inflammatory cell‐mediated liver damage. We found that serum/plasma miR‐122 correlated with alanine aminotransferase (ALT) increases in the liver damage caused by alcohol, APAP, and TLR9 (CpG)+4 (LPS) ligands. MiR‐155, a regulator of inflammation, was increased in serum/plasma in alcoholic and inflammatory liver injury. Alcohol failed to increase serum miR‐122 in TLR4‐deficient and p47phox‐deficient mice that were protected from ALD. We found the most robust increase in plasma miR‐122 in DILI and it correlated with the highest ALT levels. Consistent with the massive inflammatory cell infiltration in the liver, plasma miR‐155 and miR‐146a were significantly elevated after CpG+LPS administration. We show for the first time that, depending on the type of liver injury, circulating miRNAs are associated either with the exosome‐rich or protein‐rich compartments. In ALD and in inflammatory liver injury, serum/plasma miR‐122 and miR‐155 were predominantly associated with the exosome‐rich fraction, whereas in DILI/APAP injury these miRNAs were present in the protein‐rich fraction. Conclusion: Our results suggest that circulating miRNAs may serve as biomarkers to differentiate between hepatocyte injury and inflammation and the exosome versus protein association of miRNAs may provide further specificity to mechanisms of liver pathology. (HEPATOLOGY 2012;56:1946–1957)