Some genetic variants (polymorphisms) of the methylenetetrahydrofolate reductase (MTHFR) enzyme are considered a susceptibility factor in the development of cardiovascular diseases (CVDs). Therefore, this study aimed to investigate the relationship between MTHFR C677T polymorphism and levels of well-recognized atherogenic indices in a female population from San Luis Potosi, Mexico. A total of 340 women participated in the study, and MTHFR C677T genotypification was assessed using a RT-PCR assay. Also, Framingham risk score (FRS), Castelli risk index (CRI), and atherogenic index of plasma (AIP) were estimated. The allelic frequency detected was 0.43 for the MTHFR 677T-allele in the enrolled women. Besides, the mean value of AIP was significantly higher (p < 0.05) for individuals with the mutant genotype (TT; 0.29 ± 0.20) contrasted to AIP values detected in people with the wild-type genotype (CC; 0.15 ± 0.20) and heterozygous genotype (CT; 0.16 ± 0.20). Similar findings were observed for CRI through MTHFR C677T genotypes (4.40 ± 1.80; 3.90 ± 1.30; and 3.60 ± 0.90; for CC, CT, and TT, respectively). No significant changes were detected for FRS values across MTHFR C677T genotypes. Lastly, significant statistical associations were identified between the TT genotype and the AIP values (odds ratio: 2.15; 95% CI: 1.95–4.95; p = 0.01). No significant associations were detected between MTHFR C677T genotypes and FRS and CRI indices values. The results found in this research agree with data that support an increased CVDs risk in MTHFR 677T-allele carriers in the human population, as AIP is considered a reliable CVDs risk biomarker.