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Background: Intake of polyunsaturated fat is protective against development of coronary heart disease (CHD). Less is known about genetic variation modulating this association. The Ala12 allele of the PPARG gene decreases lipolysis of triacylglycerols in adipose tissue, resulting in accumulation of fatty acids in adipocytes. Objective: Determine whether the Pro12Ala polymorphism interacts with polyunsaturated fat intake to affect the risk of myocardial infarction (MI). Design: Cases (n=1805) with a first nonfatal acute MI and age, sex and area of residence matched population-based controls (n=1805) living in Costa Rica, were genotyped for the PPARG Pro12Ala genetic polymorphism. Polyunsaturated fat intake was determined by a validated food frequency questionnaire and by GC analysis in adipose tissue. Odds ratios (ORs) and 95% confidence intervals (95% CI) for MI were estimated using logistic regression. Results: The relative allele frequencies of the Ala12 allele were 10% in controls and 11% in cases. ORs (95% CI) for MI per each 5% increase of energy from polyunsaturated fat were 0.66 (0.53, 0.82) in Pro12/Pro12 subjects, and 0.93 (0.61, 1.42) in carriers of the Ala12 allele (p for interaction = 0.03). Increments (95% CI) of polyunsaturated fat in adipose tissue per 5% increment in dietary intake were 5.4% (4.9%, 5.9%) in Pro12/Pro12 homozygous, and 7.0% (6.0%, 8.0%) in carriers of the Ala12 variant (p for homogeneity of slopes = 0.02). Conclusions: The protective effect of polyunsaturated fat intake on MI is attenuated in carriers of the Ala12 allele of the PPARG gene.