Background: Studies have suggested that replacing saturated fatty acids (SFAs) with carbohydrates is modestly associated with a higher risk of ischemic heart disease, whereas replacing SFAs with polyunsaturated fatty acids is associated with a lower risk of ischemic heart disease. The effect of carbohydrates, however, may depend on the type consumed. Objectives: By using substitution models, we aimed to investigate the risk of myocardial infarction (MI) associated with a higher energy intake from carbohydrates and a concomitant lower energy intake from SFAs. Carbohydrates with different glycemic index (GI) values were also investigated. Design: Our prospective cohort study included 53,644 women and men free of MI at baseline. Results: During a median of 12 y of follow-up, 1943 incident MI cases occurred. There was a nonsignificant inverse association between substitution of carbohydrates with low-GI values for SFAs and risk of MI [hazard ratio (HR) for MI per 5% increment of energy intake from carbohydrates: 0.88; 95% CI: 0.72, 1.07). In contrast, there was a statistically significant positive association between substitution of carbohydrates with high-GI values for SFAs and risk of MI (HR: 1.33; 95% CI: 1.08, 1.64). There was no association for carbohydrates with medium-GI values (FIR: 0.98; 95% CI: 0.80, 1.21). No effect modification by sex was observed. Conclusion: This study suggests that replacing SFAs with carbohydrates with low-GI values is associated with a lower risk of MI, whereas replacing SFAs with carbohydrates with high-GI values is associated with a higher risk of MI.