To investigate association between the three single nucleotide polymorphisms (SNPs, rs146456111, rs143154304 and rs147260142) in cathepsin S (Cat S) and the risks of allergic asthma attack induced by the acaroid mites in the Chinese population. A case-control study was performed in 412 cases and 454 volunteers/controls to evaluate the effects of three SNPs in Cat S on the risks of asthma attack. The genotypes were determined using polymerase chain reaction (PCR) and cleaved amplification polymorphism sequence-tagged sites (PCR-RFLP). The frequencies of genotypes and alleles in these SNPs in the asthmatic group were also analyzed between the two groups. The locus of rs146456111 in Cat S gene, the allele frequency of A and C in asthmatic group were significantly different from the control group (χ2 = 184.425, P = 0.000), and the difference was significant regarding the distribution of the genotypes (AA, AC, and CC) between asthmatic subjects and normal controls (χ2 = 177.915, P = 0.000). Logistic regression analysis revealed that the AC, CC, and AC + CC genotypes were significantly increased with the risk of asthma (AC vs. AA, OR = 4.013, 95% CI = 2.989-4.751, P = 0.000; CC vs. AA, OR = 3.167, 95% CI = 2.483-3.785, P = 0.000; AC + CC vs. AA, OR = 3.418, 95% CI = 2.381-4.214, P = 0.000, respectively), compared with AA genotype. Moreover, by comparison with allele A, allele C (OR = 2.187, 95% CI = 1.743-2.281, P < 0.001) tended to increase the risk of asthma; For the locus of rs143154304, compared with the allele frequency G with A in control group, there was no difference (χ2 = 1.434, P = 0.231) in that of asthmatic group, as well as the distributions of the genotypes (AA, AG, and GG) between asthmatic subjects and normal controls (χ2 = 1.997, P = 0.369); Logistic regression analysis showed that the AG, GG, and AG + GG genotypes were no risk to asthma (AG vs. AA, OR = 0.991, 95% CI = 0.625-1.507, P = 0.968; GG vs. AA, OR = 0.812, 95% CI = 0.525-1.258, P = 0.352; AG + GG vs. AA, OR = 0.914, 95% CI = 0.612-1.366, P = 0.660, respectively) as compared with AA genotype. By comparison with allele A, G allele (OR = 0.888, 95% CI: 0.732-1.078, P = 0.231) failed to increase the risk of asthma; The allele frequencies A and G of rs147260142 in asthma group and control group showed no significant difference (χ2 = 0.162, P = 0.688), yet the distribution of the genotypes (AA, AG, and GG) in control group was different from that in asthmatic subjects (χ2 = 7.520, P = 0.023); Logistic regression analysis suggested that, in compassion with AA genotype, the AG, and AG + GG genotypes appeared to increases the risk of asthma (AG vs. AA, OR = 0.630, 95% CI = 0.439-0.903, P = 0.012; AG + GG vs. AA, OR = 0.710, 95% CI = 0.507-0.996, P = 0.047); However, the GG genotype (OR = 0.843, 95% CI = 0.576-1.234, P = 0.286) and the allele G (OR = 1.040, 95% CI = 0.860-1.258, P = 0.688) were not related to the risk of asthma. The SNP of rs146456111A/C may be susceptible to the risks of asthma in the Chinese population; however, The SNPs of rs143154304A/G and rs147260142A/G may be less likely associated with the asthma attack.