Lipoprotein lipase (LPL) is a key enzyme in lipid metabolismand is associatedwith obesity, dyslipidemias, hypertension (HTN) and type 2 diabetes mellitus (T2DM). LPL gene polymorphisms can be related with the development of cardiovascular risk factors. The present study was conducted to analyze the relationship of the HindIII and S447X polymorphisms in LPL gene with cardiovascular risk factors in Mexican families. The study population comprised ninety members of 30 Mexican families, in which an index case had obesity, were included in the study. We evaluated the body composition by bioelectrical impedance. Peripheral blood samples were collected to determine biochemical parameters. Screening for both polymorphisms was made by PCR-RFLPs. In the parents, both polymorphisms were in Hardy-Weinberg’s equilibrium. We found that the genotype T/T of HindIII was associated with diastolic blood pressure ≧ 85 mmHg (OR = 1.1; p = 0.011), whereas the genotype C/C of S447X was associated with systolic blood pressure ≧ 130 mmHg (OR = 1.2; p < 0.001), diastolic blood pressure ≧ 85 mmHg (OR = 1.3; p < 0.001), T2DM (OR = 1.3; p < 0.001) and with increase of total cholesterol (β = 23.6 mg/mL; p = 0.03). These data suggest that the HindIII and S447X LPL gene polymorphisms can confer susceptibility for the development of hypertension and T2DM in Mexican families.