Hepatitis E, the major form of enterically transmitted non-A, non-B hepatitis, is caused by hepatitis E virus (HEV). HEV is transmitted primarily by the fecal-oral route. Waterborne epidemics are characteristic of hepatitis E in developing regions of Africa, the Middle East, and Southeast and Central Asia, where sanitation conditions are suboptimal; one epidemic has also been documented in North America (Mexico) (32). HEV-associated hepatitis also occurs among individuals in industrialized countries with no history of travel to areas where HEV is endemic (6,9,18,25,36,37,39,41,52,54). Recently, accumulating lines of evidence indicate that hepatitis E is a zoonosis, and pigs or other animals may act as reservoirs for HEV infection in humans (9, 15, 20-24, 27, 39, 42, 45, 56). A significant proportion of healthy individuals in industrialized countries where hepatitis E is not endemic are seropositive for HEV antibodies (8,19,46). Therefore, several epidemiological questions remain unanswered. The success of future studies on clinical and subclinical HEV infection not only in developing countries but also in industrialized countries will greatly depend on the availability of assays that are sensitive and specific.HEV was recently classified as the sole member of the genus Hepevirus in the family Hepeviridae. The genome of HEV is a 7.2-kb, positive-sense, single-stranded RNA. It contains a short 5Ј untranslated region, three open reading frames (ORFs; ORF1, ORF2 and ORF3), and a short 3Ј untranslated region terminated by a poly(A) tract (12,34,44,53). ORF1 encodes nonstructural proteins, ORF2 encodes the capsid protein, and ORF3 encodes a cytoskeleton-associated phosphoprotein. Extensive diversity has been noted among HEV isolates, and HEV sequences have been classified into four major genotypes (genotypes 1 to 4) (37). In Japan, polyphyletic HEV strains of genotype 3 or 4 or both have been isolated from patients with sporadic acute or fulminant hepatitis E who had no history of travel to countries where this virus is endemic (1,25,30,40,41,56).The immunoglobulin M (IgM) class of antibody against HEV (anti-HEV IgM) is used as a reliable and sensitive marker of recent HEV infection (2-4, 38). However, the specificity of the solid-phase assay for anti-HEV IgM has been questioned in some cases, particularly in patients with IgMrheumatoid factors in the serum, which have activity against the Fc portion of IgG directed to HEV antigen and may elicit