BACKGROUND: Besides body mass index (BMI), other discriminators of cardiovascular risk are needed in obese patients, who may or may not undergo consideration for bariatric surgery. Coronary microvascular dysfunction (CMD), defined as impaired coronary flow reserve (CFR) in the absence of flow-limiting coronary artery disease, identifies patients at risk for adverse events independently of traditional risk factors. OBJECTIVES: The study sought to investigate the relationship among obesity, CMD, and adverse outcomes. METHODS: Consecutive patients undergoing evaluation for coronary artery disease with cardiac stress positron emission tomography demonstrating normal perfusion (N = 827) were followed for median 5.6 years for events, including death and hospitalization for myocardial infarction or heart failure. RESULTS: An inverted independent J-shaped relationship was observed between BMI and CFR, such that in obese patients CFR decreased linearly with increasing BMI (adjusted p < 0.0001). In adjusted analyses, CFR but not BMI remained independently associated with events (for a 1-U decrease in CFR, adjusted hazard ratio: 1.95; 95% confidence interval: 1.41 to 2.69; p < 0.001; for a 10-U increase in BMI, adjusted hazard ratio: 1.20; 95% confidence interval: 0.95 to 1.50; p = 0.125) and improved model discrimination (C-index 0.71 to 0.74). In obese patients, individuals with impaired CFR demonstrated a higher adjusted rate of events (5.7% vs. 2.6%; p = 0.002), even in those not currently meeting indications for bariatric surgery (6.4% vs. 2.6%; p = 0.04). CONCLUSIONS: In patients referred for testing, CMD was independently associated with elevated BMI and adverse outcomes, and was a better discriminator of risk than BMI and traditional risk factors. CFR may facilitate management of obese patients beyond currently used markers of risk.