The epidemiology and clinical manifestations of hepatitis E virus (HEV) and hepatitis A virus (HAV) are similar. However, two distinct diseases develop after exposure to each one of the viruses, which are apparently unrelated clinically. It is interesting to note that all reported epidemics and single cases of acute HEV infection indicate previous exposure to HAV. This fact leads us to hypothesize that acute HEV infection is dependent on past infection by hepatitis A virus, and that the sequential infections could not solely be explained on independent outbreaks. This hypothesis, where past HAV infection serves to support acute HEV infection, may have current practical implications, and could improve our understanding of the virology and pathophysiology of the disease.