Highly pathogenic avian influenza A(H5N1) viruses have been circulating among wild birds and are enzootic in poultry in some areas of the world with spillover to a wide range of terrestrial and marine mammals. Since 1997, sporadic animal to human, primarily poultry to human, transmission of highly pathogenic avian influenza A(H5N1) viruses has been reported in 25 countries. More recently there have been locally acquired infections in the Americas due to the 2.3.4.4b clade of the virus. Most of the recently detected human infections in the USA have been relatively mild but there have been cases of critical illness reported in several countries. In this Grand Round we present the first locally acquired highly pathogenic avian influenza A(H5N1) virus infection in Canada, which was in a 13-year-old female, who developed severe disease requiring prolonged critical care. She was infected with a clade 2.3.4.4b, genotype D1.1 virus and developed evidence of cytokine storm and received several modalities of care including combination antiviral therapy, renal replacement therapy, therapeutic plasma exchange, and invasive mechanical ventilation support with veno-venous extracorporeal life support. She recovered and was discharged home without requirement for additional support. This Grand Round describes important clinical and management considerations for critically ill patients infected with highly pathogenic avian influenza A(H5N1) virus.