Abstract: β₂-microglobulin plays an important role in the immune system of fish as an essential subunit of MHC class I molecules. We identified 30 SNPs in the β₂m gene by directly sequencing method from the parents (P₀) of Oreochromis niloticus. The results showed that 1 SNP located in 5′UTR, 17 SNPs located in the exon region (16 synonymous mutations, a synonymous mutation site), 9 SNPs located in the intron region, and 4 SNPs located in the 3′UTR. Snapshot method was used to genotype 102 resistant individuals and 102 susceptible individuals of F₁ generation. The genetic parameters such as H_e, H_o, N_e and PIC of SNPs of β₂m gene in Nile tilapia were analyzed with Popgen 32 and PIC-CALC software. The results indicated that 7 SNPs in the susceptible group were moderate polymorphism (0.25<PIC<0.5), and 25 SNPs in the resistant group were moderate polymorphism (0.25<PIC<0.5). In order to reveal its correlation with streptococcal resistant or susceptible traits, the genotype and allele frequencies of 30 SNPs in both resistant and susceptible groups of F₁ generation were analyzed by SPSS 23.0 software. These results indicated that 24 SNPs were significantly associated with the streptococcal resistant or susceptible trait (P<0.05). The results of linkage disequilibrium analysis showed that 30 SNPs formed 4 haplotype blocks and 14 haplotypes. 4 haplotypes were significantly associated with streptococcal susceptible trait, and 4 haplotypes were significantly associated with streptococcal resistance trait (P<0.05). Haplotype block 2 and block 3 were two htSNPs inβ₂m gene, which contain 4 SNPs and 13 SNPs, respectively, and highly link with each other (r²> 0.9). In this study, the SNPs and haplotypes associated with streptococcal resistant or susceptible traits can be applied to the breeding of streptococcicosis-resistant Nile tilapia as potential markers.