After rebounding from near extirpation during the organochlorine era, breeding Peregrine Falcons (Falco peregrinus, hereafter peregrines) in California are again facing adversity, this time consistent with an outbreak of a highly pathogenic avian influenza (HPAI; Alphainfluenzavirus influenzae). Following the first detection of the H5N1 variant clade 2.3.4.4b of HPAI in California wild birds in July 2022, we assembled data from long-term monitoring (2000–2025) of peregrine breeding territory occupancy in the broad vicinity of San Francisco Bay to examine possible impacts on falcon populations. Prior to the outbreak, 47 focal breeding territories had shown nearly complete occupancy by pairs (98.5% of 390 territory-years), with very few vacancies, single birds in attendance, or subadult pair members. Within 8 mo of the outbreak, occupancy had dropped to 65.1%, and 2 yr later (2025), only 36.2% of territories remained occupied. Territories were increasingly occupied by single birds after the outbreak, but it is unclear whether these were survivors or floaters attempting to fill vacant territories where both pair members had perished. The high vacancy rates also signaled an impact upon floaters (nonbreeding adults) that normally buffer breeding territory occupancy in healthy peregrine populations. From October 2022 through November 2025, 17 peregrine fatalities were diagnosed with H5N1 within our study area. Evidence that H5N1 caused these territory vacancies includes (1) the temporal coincidence of occupancy loss with the outbreak and (2) the lethality of the virus to peregrines and its confirmed presence in their prey in our study area. Our study reaffirms the value of long-term territory occupancy monitoring in this sentinel species.