<b><i>Background:</i></b> Vitiligo is an acquired, multifactorial disorder of the skin and mucous membranes. An elevated homocysteine level has been described in vitiligo. Methylenetetrahydrofolate reductase (MTHFR) and cystathionine B synthase (CBS) are major determinants of the homocysteine metabolism. <b><i>Objectives:</i></b> Determine serum homocysteine levels in vitiligo patients as well as the association between <i>MTHFR</i> (C677T, A1298C) and <i>CBS</i>gene polymorphisms and susceptibility to vitiligo in a sample of those populations. <b><i>Methods:</i></b> Homocysteine levels were estimated by radioimmunoassay while <i>MTHFR</i> (C677T, A1298C) and <i>CBS</i>gene polymorphisms were detected by the polymerase chain reaction-restriction fragment length polymorphism technique in 100 vitiligo patients and 80 healthy controls. <b><i>Results:</i></b> The homocysteine level was significantly higher in vitiligo patients than controls (<i>p</i> = 0.000). Significant differences in the genotype and allele distributions of single nucleotide polymorphisms of the <i>MTHFR</i> (C677T, A1298C) with the mutant genotypes are more common in the controls than patients (<i>p</i> = 0.001, 0.029, respectively). <i>CBS</i> gene mutant genotypes and alleles are more common in vitiligo patients than controls (<i>p</i> = 0.002). <b><i>Conclusion:</i></b> <i>CBS</i>and<i> MTHFR</i>gene polymorphisms may play a major role in the genetic susceptibility to vitiligo.