The molecular characteristics of hepatitis A virus (HAV) have been studied widely though there is a paucity of data on the correlation with virological and serological findings. In the present study, the whole genome of an Indian HAV strain associated with Guillain–Barré syndrome (GBS) was characterized vis‐à‐vis two other Indian HAV genotype IIIA strains, associated with a self‐limiting disease. The percentage nucleotide divergence displayed by the Indian strains (CP‐IND, PN‐IND, and GBS‐IND) varied from 3 to 6, whereas the percentage amino acid divergence varied from 0.1 to 0.7 as compared to the other HAV IIIA strains (n = 5) available in the GenBank. The GBS‐IND strain showed an increased rate of nonsynonymous substitutions as well as a larger number of unique and heterologous amino acid substitutions compared to the HAV IIIA GenBank strains. These amino acid substitutions in the GBS‐IND strain were detected in a nonstructural protein (2C‐251F) and the B‐cell epitope regions of structural proteins (VP1‐29E, VP1‐91S, VP3‐50Y, and VP4‐5S). In a comparative analysis of HAV strains, homology‐based models of the capsid proteins indicated a localized alteration in the surface charge distribution on the VP1 protein of GBS‐IND strain and involvement of its unique amino acid substitutions in the predicted antigenic determinants. Overall, the study suggests that the unique amino acid substitutions in the GBS‐IND strain may have contributed to neutralization escape of the virus leading to a longer duration of viremia. J. Med. Virol. 82:913–919, 2010. © 2010 Wiley‐Liss, Inc.