Infection with the recently emerged pandemic influenza A(H1N1) virus causes mild disease in the vast majority of cases, but sporadically also very severe disease. A specific mutation in the viral haemagglutinin (D222G) was found with considerable frequency in fatal and severe cases in Norway, but was virtually absent among clinically mild cases. This difference was statistically significant and our data are consistent with a possible causal relationship between this mutation and the clinical outcome.