Studies have revealed that elevated homocysteine levels can cause damage to motor neurons through multiple neurotoxic mechanisms, thus leading to the pathogenesis of amyotrophic lateral sclerosis (ALS). One way by which homocysteine levels are increased in the body is the consequence of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms. Therefore, to address this question, we studied the MTHFR C677T and A1298C polymorphisms in 437 sporadic ALS (SALS) and 439 healthy controls to learn whether they were associated with SALS. The overall SALS were not associated with MTHFR C677T and A1298C polymorphisms (chi(2) = 1.378; p = 0.502; chi(2) = 1.304; p = 0.521, respectively). However, when we stratified results in terms of gender, we found that the MTHFR C677T polymorphism (chi(2) = 6.376; p = 0.041), T677T genotype (chi(2) = 5.508; p = 0.019; odds ratio [OR] = 2.561; 95% confidence interval [CI] = 1.142-5.744), C677C/A1298A (chi(2) = 5.216; p = 0.022; OR= 0.424, 95% CI = 0.199-0.900), and T677T/A1298A (chi(2) = 6.639; p = 0.010; OR= 2.900; 95% CI = 1.252-6.717) compound genotypes were associated with SALS in female patients only. Moreover, stratification of SALS according to the onset of disease indicated that there was no association between MTHFR C677T (chi(2) = 1.565; p = 0.457; A1298C chi(2) = 3.461; p = 0.177) polymorphisms and overall spinal onset SALS. Further stratification analysis according to gender revealed that there was a remarkable association between MTHFR C677T (chi(2) = 9.728, p = 0.008), T677T genotype (chi(2) = 7.820; p = 0.005; OR= 3.126; 95% CI = 1.361-7.178) and T allele (chi(2) = 5.000; p = 0.025; OR= 1.711; 95% CI = 1.067-2.745), and T677T/A1298A compound genotype (chi(2) = 9.108; p = 0.003; OR= 3.540; 95% CI = 1.494-8.387) and spinal onset female SALS only. Likewise, there was also association between MTHFR A1298C polymorphism (chi(2) = 5.946; p = 0.051) and the C1298C genotype (chi(2) = 5.282; p = 0.022; OR = 2.524; 95% CI = 1.125-5.658), and the C677T/C1298C compound genotype (chi(2) = 7.155; p = 0.007; OR= 1.045; 95% CI = 0.983-1.112) and bulbar onset SALS only in women. In conclusion, the evidence we provide here clearly shows that MTHFR C677T and A1298C polymorphisms are genetic risk factors for SALS in women in a gender-specific manner whether they are of spinal or bulbar onset.