On 18 February 2021, the National IHR Focal Point for the Russian Federation notified WHO of detection of avian influenza A(H5N8) in seven human clinical specimens. These are the first reported detection of avian influenza A(H5N8) in humans. Positive clinical specimens were collected from poultry farm workers who participated in a response operation to contain an avian influenza A(H5N8) outbreak detected in a poultry farm in Astrakhan Oblast in the Russian Federation. The laboratory confirmation of the seven specimens were performed by the State Research Centre for Virology and Biotechnology VECTOR (WHO H5 Reference Laboratory). The age of seven positive cases ranged between 29 to 60 years and five were female.