Epidemic outbreaks of avian influenza (AI) virus H5N1 have been frequently reported in Egypt during the last nine years. Here we investigate the involvement of AI H5N1 in outbreaks of acute respiratory disease that occurred in several commercial chicken farms in Egypt in 2011, and we describe to the pathology caused by the virus in the course of the outbreak. Twenty-one chicken farms with history of acute respiratory symptoms and high mortalities were screened for AI H5N1. Virus identification was based on hemagglutination inhibition test, and PCR detection and sequencing of the hemagglutinin and neuraminidase genes. Virus distribution was determined by immunohistochemical staining of AI antigens in organs of infected birds. Standard H &E staining was performed for histological examination of affected organs. Eighty-one % of the examined birds, representing 100% of the screened farms, were positive for AI H5N1 virus. Phylogenetic analysis of the hemagglutinin and neuraminidase genes of the isolated virus reveals its affiliation to clade 2.2.1. Viral antigens were localized in the endothelial cells of the heart, liver, lungs and skin, where pathological lesions including congestion, hemorrhages, multifocal inflam- mation and necrosis were concurrently observed. According to the pattern of the viral antigen and lesion distribution in the visceral organs, we suggest cardiovascular and circulatory failures as the probable cause of death during these outbreaks. In conclusion, the present study further confirms the epidemic status of AI H5N1 virus in Egypt and reveals the highly pathogenic nature of the local isolates.