Fulminant hepatitis is a severe complication of hepatitis A virus infection. Its mechanism is unknown. Liver transplantation can be necessary, but spontaneous recovery is frequent. There are no data on the level of viral replication according to the clinical form of hepatitis A. We reviewed the files of 50 patients with acute hepatitis A. Nineteen patients had fulminant hepatitis (defined by encephalopathy and factor V <50%), and, from them, 10 patients underwent transplantation. Hepatitis A virus (HAV) RNA was quantified by real-time PCR on sera obtained at admission. The genotype was determined by phylogenetic analysis of HAV RNA. HAV RNA was detected in serum by RT-PCR in 39 out of 50 patients. Encephalopathy and low factor V level were significantly related to female gender, HAV PCR negativity (9/19 vs. 5/31, respectively; P = .03), a low serum HAV RNA level (log, 3.6 ± 0.6 vs. 4.4 ± 0.9, respectively; P = .02), genotypes other than IA, and acetaminophen intake. In multivariate analysis, low or undetectable HAV viral load and a high bilirubin level were independently associated with both low factor V levels and fulminant hepatitis and also with death or transplantation. In conclusion, HAV-related liver failure is due to an excessive host response associated with a marked reduction in viral load. Serum HAV RNA assay could be of help in the management of severe hepatitis A.