Single nucleotide polymorphisms (SNPs) are useful genetic markers to investigate the onset of multiple sclerosis (MS). A genome wide association study identified 7 SNPs associated with interferon-β therapy response, however, not with MS risk in a Spanish population. To investigate these findings in a different cohort, the 7 SNPs were investigated in an Arabian Gulf population. The SNPs were analyzed in 268 subjects (156 patients and 112 healthy volunteers) from the Arabian Gulf region using restriction fragment length polymorphism-polymerase chain reaction (PCR) and KBioscience Competitive Allele Specific PCR genotyping methods. Associations between the SNPs and MS were investigated using logistic regression. The present study observed, for the first time, that in an Arabian Gulf population, the ZFAT rs733254 polymorphism (T>G) is a gender-specific risk marker for MS. ZFAT was associated with MS in women but not in men. The G variant was highly associated with the risk of MS [odds ratio (OR)=2.38 and 95% confidence interval (CI), 1.45–3.91); P=0.0014]. Whereas variant T was a significantly protective factor [OR=0.420 (95% CI, 0.25–0.69); P=0.0014, recessive model]. The findings of the present study provide a genetic basis for the gender-associated susceptibility to MS. In addition, this MS-associated rs733254 SNP may predict MS onset in females from the Arabian Gulf population.