Background <p>The most prevalent type of acquired depigmentation disorder is vitiligo, which is characterized by the development of white spots on the skin, hair, and mucous membranes due to melanocyte loss. It is a polygenic and multifactorial disease with complicated genetic and environmental pathogenesis. The onset and progression of vitiligo are strongly influenced by both genetic and environmental variables, including neurological effects, oxidative-antioxidative stress, and immune dysfunction.</p> Methods and results <p>The polymorphism (rs2670660) in the NLRP1 gene was analyzed in 110 patients with vitiligo and 110 healthy controls matched for age and sex. Tetra-ARMS PCR was used to determine the genotypes, and Sanger sequencing was employed to validate the three genotypes. Initial genotype analysis revealed significant differences in genotype distribution between cases and control (<i>p</i> = 0.035). Further analysis of the genotype data showed that the frequency of the GG genotypes was significantly higher in vitiligo cases than in controls under the recessive model (odds ratio [OR] 2.647; 95% confidence interval [CI] 1.230–5.695; p-value = 0.011). Moreover, the prevalence of the G allele was also significantly higher in the patient group (<i>P</i> = 0.019, OR = 1.595, 95% CI = 1.081–2.353).</p> Conclusion <p>In conclusion, the <i>NLRP1</i> polymorphism rs2670660 is significantly associated with the onset of vitiligo in the Pakistani population.</p>