The association between a particular mutation in the HA1 subunit of the influenza virus haemagglutinin, D222G, and severe and fatal disease in cases of influ-enza A(H1N1)pdm09 in Norway during the 2009 pan-demic was investigated using pyrosequencing. The prevalence of the variant among fatal cases was 8/26 and among severe non-fatal cases 5/52. No D222G mutations were found among the 381 mild cases. This difference could not be attributed to sampling differ-ences, such as body location of sampling, or duration of illness. In cases with mutant virus where clinical specimens from different days of illness were avail-able, transition from wild-type to mutant virus was commonly observed (4/5), indicating that the mutant virus emerged sporadically in individual patients. In patients with paired samples from both the upper and lower respiratory tract (n=8), the same viral geno-types were detected in both locations. In most of the D222G cases (11/13), the mutant virus was found as a quasispecies.