Histones are central components of nucleosome and chromatin, which play critical roles in diversifying chromatin structure, transcriptional regulation, ontogenesis and so on. Although there were a lot of reports on the effects of piscine histones in the development, gene transcription regulation and anti-microbial properties of histone-derived antimicrobial peptides, the roles of histone nucleotide polymorphism in pathogen infection have not been reported in any species of vertebrates. In the present study, we found that nucleotide polymorphisms were abundant in zebrafish (Danio rerio) and grass carp (Ctenopharyngodon idella) H2A. There was 90%-100% identity among D. rerio and C. idella H2A variants at the nucleotide level. At most 3 sites of amino acid mutation existed between H2A variants from D. rerio or C. idella. The results from the in vitro and in vivo studies showed that the nucleotide polymorphism of D. rerio and C. idella H2A significantly affected the antibacterial activities of H2A. Furthermore, the overexpression of D. rerio antibacterial H2A variants in D. rerio embryos and/or larvae not only has the immune enhancement effect, but also enhances the resistence of D. rerio larvae against Edwardsiella piscicida infection. The present study established the immunological basis of histone H2A variants with nucleotide polymorphism in disease susceptibility or disease resistance.