Introduction and Aims: Hepatitis E virus (HEV) is a hepatotropic RNA virus with four genotypes. Genotypes 1 and 2 infect only humans, whereas genotypes 3 and 4 also infect several mammalian species. HEV infection is common in several developing countries; in these areas, it has primarily a waterborne, human-to-human transmission, and causes acute hepatitis. In recent years, sporadic human HEV infections have been reported from developed countries; these appear to be related to zoonotic transmission, are with genotype 3 or 4 HEV, and are also associated with chronic hepatitis among immunosuppressed persons. In India, a hyperendemic region, genotype 1 and 4 HEV have been isolated from humans and pigs, respectively, and further data are needed to determine whether non-1 HEV genotypes cause human disease. Method: Sera from 300 patients with acute sporadic hepatitis E (typical clinical picture and detectable serum IgM anti-HEV) were tested for HEV RNA using a Taqman real-time polymerase chain reaction assay. For specimens with detectable HEV RNA, a segment of HEV ORF1 gene was amplified and sequenced in both directions. The 307-bp sequences obtained after trimming the primer regions were aligned with those from various HEV genotypes and subgenotypes, and analyzed using phylogenetic tools. Results: Of the 136 isolates that had detectable HEV RNA, sequencing was done for 71. These sequences showed homology of 88.3% to 100% with each other. All the 71 patient sequences clustered with genotype 1a prototype sequences, with homology rates of 90.3% to 95.3%. None of the patient sequences showed similarity with genotype 2, 3 or 4 HEV; the homology of patient sequences with prototype genotype 2, 3 and 4 HEV sequences was 68.4-74.6%, 60.7-69.8% and 58.5-67.9%, respectively. Conclusion: In India, genotype 1a is the most prevalent HEV genotype responsible for disease, and human infection with other HEV genotypes is either rare or non-existent.