The dissociation capability of the hemagglutinin precursor (HA0) to HA1 and HA2 is related to the degree of pathogenicity of influenza virus. The H5 strains that contain polybasic residues inserted at the cleavage site by the RXR/KR motif are recognized by the subtilisin-like proteases and are associated with a high pathogenicity in humans. The available predicted amino acid sequences of the H5 subtype isolated from avian and human hosts were collected and aligned. As a result, most of the insertion types in viruses isolated from humans were also found in avian H5 isolates, but not in vice versa. With avian-to-human transmission, the unique avian H5 insertion types with the RXR/KR recognition motif were predicted as potential new candidates for the next highly pathogenic avian influenza H5 in humans. Additionally, at most the two basic residues extended from the recognition motif were found to be optimum fit with the furin-like enzyme. © 2012 Wiley Periodicals, Inc.