Antiviral susceptibility testing and reporting of viruses carrying amino acid substitutions conferring antiviral drug resistance is essential to assess the spread and clinical impact of these viruses. Here, we report on a patient who was infected with a primarily oseltamivir-resistant influenza A (H1N1pdm09) virus following allogeneic stem cell transplantation and rituximab treatment. Under prolonged virus replication and zanamivir therapy the neuraminidase amino acid substitutions H275Y and I223R were detected conferring high-level resistance to oseltamivir and cross-resistance to zanamivir. The emergence of these amino acid changes has been reported rarely worldwide and has been associated with fatal clinical outcomes. The patient survived the influenza infection after 170 days of follow-up.