BACKGROUND: High-fat meals and elevated triglyceride levels are associated with cardiovascular disease. In recent studies of brachial artery vasoactivity, a single high-fat meal reduced endothelial function in young healthy men. It is unknown whether coronary microcirculation is affected after high-fat meals. OBJECTIVE: To evaluate change in coronary flow reserve after a single high-fat meal. DESIGN: Controlled interventional study. SETTING: University hospitals. PATIENTS: 15 young healthy men (mean age [+/-SD], 29 +/- 4 years). INTERVENTION: Coronary flow reserve was determined by using transthoracic Doppler echocardiography before and after consumption of a high-fat meal in all 15 men and before and after consumption of a low-fat meal in 5 of 15 men. MEASUREMENTS: Coronary flow reserve, lipid levels, and hemodynamic characteristics. RESULTS: In all men, triglyceride levels increased significantly from baseline 5 hours after the high-fat meal, from 1.1 mmol/L to 2.8 mmol/L (100 mg/dL to 250 mg/dL) (P < 0.001). Average coronary flow reserve was 4.02 before and 3.30 5 hours after the high-fat meal (decrease, 18% [95% CI, 13% to 23%]). In the 5 men who received both meals, mean coronary flow reserve decreased by 0.79 after the high-fat meal and increased by 0.07 after the low-fat meal (difference, -0.86 [CI, -1.36 to -0.37]; P = 0.03). Mean triglyceride levels increased by 1.6 mmol/L (140 mg/dL) after the high-fat meal and 0.1 mmol/L (10 mg/dL) after the low-fat meal (difference, 1.5 mmol/L [CI, 0.3 to 2.7 mmol/L], 130 mg/dL [CI, 23 to 236 mg/dL]; P = 0.03). CONCLUSIONS: Coronary flow reserve decreased after a single high-fat meal in young healthy men. High-fat meals may be detrimental to coronary microcirculation.