Background: Hepatitis E (HE) is prevalent in developing countries in both epidemic and sporadic forms and is characterized by high mortality during pregnancy. miR-122, the major hepatic microRNA has been shown to be modulated during liver diseases. Lack of data in HE led to investigations in non-pregnant (NPR) and pregnant (PR) patients. Results: Self-recovering NPR patients and pregnant women presenting with clinical (PR-acute) or subclinical (PR-SC) HE and respective healthy controls were studied. Serum samples were tested for miR-122 levels using qRT-PCR. Acute-phase, NPR patients circulated lower miR-122 levels, reducing further during convalescence. In contrast to previous reports, circulating miR-122 levels did not correlate with serum aminotransferase (ALT). In PR-acute patients, miR-122 levels were significantly lower that reflected pregnancy status and not HEV effect. In PR-SC patients, miR-122 levels were lower than the pregnant controls and reduced further when examined one month apart. A pregnant, fulminant HE patient circulated very high miR-122 levels that increased further during convalescence. Correlation analysis of miR-122 and circulating cytokines showed moderate correlation with CCL2 (subclinical, pregnant) and IL-6 (NPR). This first report revealed downregulation of circulating miR-122 levels in self-recovering NPR-acute patients despite liver damage (raised serum ALT) suggestive of alternate mechanism of secretion in blood. Conclusion: HEV infection during pregnancy led to differential modulation of serum miR-122 levels that correlated with clinical presentation. Utility of miR-122 as a prognostic marker for severe disease during pregnancy needs to be evaluated.