Objective To reveal evolution characteristics and antigenic epitope variabilities of hemagglutinin (HA) gene of H3N2 viruses in Guangdong during 2014-2015.Methods The HA gene nucleotide sequence of influenza H3N2 virus isolated during 2014-2015 in Guangdong Province was selected by spatial-temporal distribution.The HA gene nucleotide sequences were compared with global HA genes downloaded from GenBank and GISAID and the gene nucleotide mutations were analyzed.The phylogenetic tree and the entropy chart were conducted.Results Compared with HA gene of vaccine strain A/Texas/50/2012,the substitutions of 25 amino acid sites occurred in the HA gene of the 17 Guangdong strains during 2014 to 2015.The epitope A,B,D and E of the HA1 gene developed mutations,which involved 11 amino acid sites.One glycosylation site deletion occurred in A/Guangdong/ 55/2015 in virtue of the N38K site mutation.The high mutation site was at 175 with entropy value of 1.16.The 363 site might be the positive selection while the 368 and 425 sites might be the negative selection sites by comprehensive evaluation of the screening results of the single likelihood ancestor countincy (SLAC),fixed effects likelihood (FEL) and internal fixed-effects likelihood (IFEL) model.Conclusions The mutations emerge in the epitopes A,B,D and E of HA gene of the Guangdong H3N2 stains.Evolution at 363 site is positive selection while those at 368 and 425 sites are negative selection.The mutation accumulation might lead to the epidemic of influenza H3N2.