The association between small size at birth and increased risk of cardiovascular disease in adulthood is well established. This relationship is commonly interpreted according to the "thrifty phenotype hypothesis," which states that the association is generated by a mismatch between fetal and postnatal nutrition. Empirical support for an interaction between impaired fetal growth and later overnutrition is, however, sparse and partly conflicting. The Stockholm Heart Epidemiology Program is a population-based case-control study of risk factors for acute myocardial infarction (MI); data were available for 1058 cases and 1478 controls. Using logistic regression, we studied the effect of size at birth, and its interactive effect with body mass index (BMI), at 3 occasions in adulthood, on the risk of MI. Biologic interaction was estimated with the synergy index. Very low birth weight for gestational age was associated with increased risk of MI (odds ratio [OR] = 2.0; 95% confidence interval [CI] = 1.4-2.9; attributable fraction = 5%). In nonfatal cases, adjustment for waist-hip ratio, insulin resistance, blood pressure, and lipids reduced the point estimate somewhat. Low birth weight for gestational age in combination with high BMI at the time of the MI produced an OR of 10.8 (3.6-31.8) for MI compared with normal birth weight and normal BMI; the synergy index was 6.5 (95% CI = 1.8-24.0). The synergism between small size at birth and high adult BMI supports the thrifty phenotype hypothesis. However, this mechanism seems to pertain to only a small fraction of the acute MI cases, implying minor public health importance.