BACKGROUND: The purpose of this study was to examine effect modifiers of the relationship between family history of diabetes, a proxy for genetic predisposition, and the metabolic syndrome. METHODS: Subjects were a cross-sectional sample of 205 Mexican-Americans patients of the San Ysidro Health Center in San Diego County. Self-reported parental history of diabetes was examined as a risk factor for individual metabolic syndrome traits (hyperglycemia, hypertension, abdominal obesity, hypertriglyceridemia and low HDL-cholesterol) and a composite phenotype, defined both by standard modified National Cholesterol Education Program- Adult Treatment Panel III (NCEP-ATPIII) criteria and using principal components analysis, in age and sex-adjusted multiple logistic and linear regression models. RESULTS: Family history of diabetes was most strongly associated with individual traits of hyperglycemia (P = .0002) and low HDL-C (P = .001) and conferred a significant increased odds of metabolic syndrome defined by both NCEP-ATPIII criteria (odds ratio 3.57, 95% confidence interval 1.82, 7.01; P = .0002) and by principal components analysis (P = 0.003). Moreover, the family history association with metabolic syndrome was modified by number of years living in the United States (interaction P = .04). This same effect was not seen for diabetes (P = .19). CONCLUSIONS: The results of our study support a common etiology for at least some components of the metabolic syndrome, especially hyperglycemia and low HDL-cholesterol, the basis of which may be genetic. Moreover, the effect of genes on these traits may be modified by longer duration in the United States, supporting the concept of gene-environment interaction in the development of the metabolic syndrome.