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Influenza virus (H5N1) is highly contagious disease, which attacks the respiratory tract in humans. The deaths of six people in Hong Kong in 1997 from an H5N1 virus infection was the first indication that a purely avian influenza virus could cause respiratory disease and death in human. The aim of current study was to observe changes of epidemiological parameters of the infected patients, and the behaviour of virus outbreak over two decades of avian influenza virus (H5N1) from 1997 to April 2017. Data of the current study was obtained from WHO (World Health Organization) daily outbreak reports and then computerized and analyzed. It included 826 cases from 1997 to last case in April 2017 for this study. Most of the studied cases, their ages were less than 16 years (n=366), and spread in 16 countries, the top three countries prevalence were Egypt (n= 356), Indonesia (n= 175), and Vietnam (n=87) respectively. The most years of cases incidence were 2015 (n= 147) and 2006 (n=122). Most of cases were recorded in January (n=180), February (n=149), and March (n=143) respectively. Case fatality rates were 50.7%. In conclusion most cases were in second decade than first decade of (H5N1) outbreak, but death were more in first decade, Also most cases were in low temperature seasons and in very young children but death were more in adults. In first decade, morbidity were more in Asia countries like China, Vietnam, and Indonesia but in second decade, mortality were more in North Africa (Egypt). However, cases were more in Egypt than Indonesia but deaths were more in Indonesia. H5N1 virus must be currently studied and its controlling is highly requested. [ABSTRACT FROM AUTHOR]