Introduction: Coronary angiography falls short in accurately evaluating the coronary microcirculation. Fortunately, a new comprehensive invasive hemodynamic assessment method, which uses coronary flow reserve (CFR) and the index of microvascular resistance (IMR), provides enhanced diagnostic capabilities. Objective: We present our early real-world experience with invasive hemodynamic assessment of the coronary microvasculature in symptomatic patients with non-obstructive coronary artery disease (CAD) from the first US Coronary Microvascular Disease Registry (CMDR). Methods: The CMDR is a prospective, multi-center, standardized registry of patients with angina and non-obstructive CAD who underwent invasive hemodynamic assessment of the coronary microvasculature using the Coroventis CoroFlow Cardiovascular System (Abbott Laboratories, Chicago, Illinois). Comprehensive assessments, including resting full-cycle ratio (RFR), fractional flow reserve (FFR), CFR, and IMR, were performed on all patients. Results: The first 156 patients enrolled in the CMDR were analyzed; their mean age was 62.4 years and 65.6% were female. A substantial proportion (31.8%) of patients presented with a Canadian Cardiovascular Society Angina Score of 3 or 4. CMD was diagnosed in 39 of 154 patients (25.3%), with mean RFR of 0.89±0.43, mean FFR of 0.93±0.08, mean CFR of 1.8±0.9, and mean IMR of 36.26±19.23. None of the patients experienced in-hospital adverse events. Conclusions: Early results from CMDR patients show that invasive hemodynamic assessment of the coronary microvasculature is safe and effective for suspected CMD. Tailored medical therapy for microvascular angina was provided to diagnosed CMD patients. With ongoing patient enrollment, the CMDR aims to contribute valuable insights to the growing evidence base for CMD.