BACKGROUND: The antigen processing 1 () and proteasome 20S subunit beta 9 () genes are associated with strong susceptibility to many autoimmune diseases. Here, we explored whether genetic variants, individually or combined, affected susceptibility to the complex, autoimmune-based skin disorder vitiligo. METHODS: Samples of genomic DNA from buccal cells of 172 patients with vitiligo and 129 healthy controls were analyzed using genotyping assays for the rs1135216 (A>G) and rs17587 (A>G) single nucleotide polymorphisms (SNPs). SNPStats software (https://www.snpstats.net) was utilized to choose the best interactive inheritance mode for selected SNPs. RESULTS: The genotype frequencies for the rs1135216 and rs17587 SNPs were in Hardy-Weinberg equilibrium for cases (= 0.11 and = 0.10, respectively) but not for controls (< 0.05). The rs1135216 (D637G) and rs17587 (R60H) SNPs increased the risk of vitiligo four-fold and two-fold, respectively (odds ratio [OR]= 4.6; 95% confidence interval [CI], 3.2-6.5; < 0.0001 and OR= 2.2; 95% CI, 1.5-3.1; < 0.0001). The recessive model (G/G-D/G versus D/D) and the codominant model (R/R versus R/H) were the best models of inheritance for the rs113526 and rs17587 SNPs, respectively (OR= 16.4; 95% CI, 2.0-138; = 0.0006 and OR= 1.7; 95% CI, 0.3-1.8; = 0.013). Vulgaris, focal vulgaris, and acryl/acrofacial were the most common vitiligo subtypes in our sample (51%, 21%, and 19%, respectively). Heterozygous rs113526 (637D/G) and rs17587 (60R/H) were the most common genotypes in most vitiligo subtypes. The heterozygous 637D/G genotype and the 637G variant allele were significantly more common in patients with active disease than in patients with stable disease (= 0.000052 and = 0.0063, respectively). CONCLUSION: Our findings suggest a crucial role for rs1135216 and rs17587 in the risk and progression of vitiligo in the Saudi community. Genomic analyses are needed to identify more candidate genes and more genetic variants associated with vitiligo.