The recent discovery of a presumably Japan-indigenous hepatitis E virus (HEV) strain (JRA1) spurred analysis of additional isolates from 7 cases of acute sporadic hepatitis E infection. Comparison of a 326-nucleotide region from open-reading frame 1 indicated that 1, 3, and 3 isolates segregated to genotypes I, III, and IV, respectively. Six patients had not traveled abroad recently. One patient had traveled to Hawaii 1 month before becoming ill, and the nucleotide sequence of the HEV isolate infecting her resembled those of US isolates (89%-91% nucleotide identity). However, the isolate was even more homologous to 2 other Japanese isolates (95%-97% nucleotide identity), suggesting that it is more likely a domestic, rather than an imported, strain. Three genotype IV isolates from Japan also had a higher homology to each other (100% amino acid identity) than to 2 Chinese isolates (97%-98% amino acid identity). These findings suggest that HEV strains of at least 3 different genotypes have already made inroads and are spreading in Japan.