Introduction. The role of leptin in humans is an essential factor in the pathophysiology of obesity and type 2 diabetes (T2D); and it is also related to their comorbidities. The objective of this study was to determine the influence together of rs7799039 (-2548G>A) LEP and rs1137101 (223Gln>Arg) LEPR polymorphisms, as well as biochemical and somatometric parameters, as risk factors for T2D. Material and Methods. A cross-sectional case-control study with a control group and a case group. Both groups were matched by age, sex, and body mass index. The genes were amplified by conventional PCR and were genotyped by restriction fragment length polymorphism (RFLP) analysis. Polymorphims were validated using real-time PCRand TaqMan® probesin triplicate. Sample size was determined using an equation for cases and controls. Genomic DNA was isolated from leukocytes of peripheral blood samples using the DTAB/CTAB method and gene amplification wasperformed by conventional PCR. The presence of the polymorphisms was validated using real-time PCR and Applied Biosystems® TaqMan® probes C_3001671_10 for leptin and C_8722581_10 for leptin receptorpolymorphisms. Results. The polymorphism LEP rs7799039 in genotypes G/A, and A/A, was associated with T2D [OR=2.23 C=1.13 to 4.37 and OR=2.62 CI=1.27 to 5.40, respectively]. Additionally, polymorphism rs1137101 in genotypes A/G and G/G was associated with T2D (OR=0.35, IC=0.17 to 0.72 and OR=4.7, CI=2.29 to 9.62, respectively). Analyzed together, the combined genotypes GA-2548/GG223 (OR=7.61 CI=2.02 to 28.67) and AA-2548/GG223 (OR=3.53 CI=1.14 to 10.92) were found to be strongly associated with T2D. Remarkably, the combined genotype GG-2548/AA223 and AA-2548/AA223 tended to be a protective factor against T2D (OR=0.28, CI=0.08 to 0.47 and OR=0.26, CI=0.08 to 0.81). Conclusions. LEP and LEPR polymorphisms are associated with T2D in this population. Notably, the combined genotypes GG-2548/AA223 and AA-2548/AA223 are factors associated with a reduced risk of T2D, while the GA-2548/GG223 and AA-2548/GG223 genotypes combined conform a risk factor for T2D. Our findings warrant future cohort studies.