dataset found a relatively high seroprevalence (21%) of hepatitis E virus (HEV) infection in the U.S. general population. Using data obtained within the NHANES 2009-2010 survey, where a high performance assay for HEV was used, we estimated the weighted seroprevalence of HEV infection among U.S. individuals 6 years and older. We also evaluated factors associated with HEV seropositivity. A total of 8,814 individuals were included in the analysis. The median age of study participants was 37 years (interquartile range [IQR] 17-58 years), with 51.2% being female. The weighted national seroprevalence of HEV was 6% (95% confidence interval [CI] 5.1%-6.9%). About 0.5% of those with HEV had evidence of recent exposure (immunoglobulin M-positive). In the univariate analyses, factors associated with HEV seropositivity were increasing age (P-trend < 0.001), birth outside of the U.S., Hispanic race, and "meat" consumption (>10 times/month). No significant association was observed with low socioeconomic status, water source, or level of education. In the multivariate analysis, only older age remained predictive of HEV seropositivity. Conclusion: The weighted national seroprevalence of HEV in the U.S. is much less than previously reported. Using data obtained with a high performance assay, the seroprevalence of HEV was estimated at 6.0% in the U.S. Based on these results, the seroprevalence of HEV is only one-third as high as previously reported. (HEPATOLOGY 2014;60:815-822) H epatitis E virus (HEV) is the most common cause of acute viral hepatitis and jaundice worldwide. 1,2 It is a major public health problem in developing countries, where sporadic infections and epidemics of HEV occur periodically. [3][4][5][6] The prevalence of antibodies to HEV (anti-HEV) among adults in developing countries ranges from 30% to 80%. Infection is mainly transmitted by way of a fecal-oral route, usually through contaminated drinking water or food. HEV infection typically causes an acute, self-limited hepatitis. HEV infection can, however, be particularly severe in infants under 2 years of age, people with preexisting chronic liver disease, and is associated with 10% to 25% mortality in pregnant women. 5,[7][8][9] HEV infection is increasingly recognized in the developed world, where it was previously thought to be uncommon. Cases were often attributed to travel in the tropics and subtropics. 10 Recent studies indicate that most cases of HEV in the developed world are, in fact, locally acquired (autochthonous), 1,11-16 possibly related to zoonotic transmission. The reported prevalence of anti-HEV in low-incidence countries varies widely, ranging from <1% to >20%.