Hepatitis E virus (HEV) is evolving as a major global threat to public health, including in developed countries. We partially sequenced the ORF 2 capsid protein genes of HEV genomes from patients with acute liver failure, including pregnant women in the northern part of India. Five unique synonymous substitutions and one non-synonymous substitution, along with a novel mutation, P259S, in the capsid gene, were identified that might be associated with the poor outcome in the patients. Phylogenetic analysis revealed that the isolates belonged to genotype 1 with subtype 1a. The significance of these findings for disease pathogenicity needs to be investigated further.