An outbreak of highly pathogenic avian influenza A (H5N6) virus occurred between November 20, 2016 and March 1, 2017 in poultry farms, in the Gyeonggi Province, Republic of Korea. To identify the risk of transmission of H5N6 to depopulation workers, active and passive surveillance was conducted. Virological testing of respiratory swabs with real-time reverse transcription-polymerase chain reaction was performed for workers who reported respiratory symptoms. Among 4633 depopulation workers, 25 reported respiratory symptoms, but all tested negative for H5N6. Personal protective equipment in addition to antiviral prophylaxis was adequate to limit transmission of H5N6 from poultry to humans.