Avian influenza A virus (IAV) H5N1 is an emerging threat of human pandemic. We describe a 71-year-old man who died of H5N1 pneumonia in Louisiana and whose blood contained autoantibodies neutralizing type I IFNs (AAN-I-IFNs), including the 12 IFN-α subtypes (1–10 ng/ml) and IFN-ω (100 pg/ml). Causality between these AAN-I-IFN and lethal outcome of avian influenza in this patient is based on (1) our previous report that AA-I-IFN underlie about 5% of cases of critical pneumonia triggered by seasonal influenza viruses in three cohorts, (2) the rarity of this combination of AAN-I-FNs in individuals over 70 years old (<1%), and (3) the rarity of lethal avian influenza among infected individuals (<1%). AAN-I-IFNs underlie a growing number of severe viral diseases, from arboviral encephalitis to viral pneumonia, particularly in the elderly. This case suggests they can also underlie life-threatening avian H5N1 influenza. The presence of AAN-I-IFN may facilitate infection, replication, and adaptation of zoonotic IAVs to humans and, therefore, human-to-human transmission.