Backgrounds: Anomalous origin of right coronary artery (RCA) from left coronary cusp (LCC) has become increasingly recognized with wider use of imaging technologies. As this anomaly can be associated with myocardial ischemia and sudden cardiac death, surgical repair is recommended in cases with clinical events. However, the clinical relevance and management of incidentally found anomalous origin of RCA from left LCC are still ill-defined. Objectives: This study was performed to evaluate the long-term clinical outcome of anomalous origin of RCA from LCC and to assess the anatomical and physiologic significance of this anomaly using dobutamine stress-fractional flow reserve (FFR) and intravascular ultrasound (IVUS). Methods: Total 297 patients with anomalous origin of RCA from LCC were enrolled in from three different hospitals. IVUS and dobutamine stress-FFR were performed in 31 consecutive patients enrolled since September 2009. FFR was measured at baseline and after incremental intravenous dobutamine doses. FFR ���0.80 was considered significant. IVUS was analyzed in an independent core laboratory blinded to the results of FFR. Results: IVUS and FFR measurements were successful in 31 patients. Mean FFR was 0.91짹0.06 at baseline and 0.89짹0.01 with dobutamine challenge (p=0.023). FFR became significant in 3 patients after dobutamine challenge. All the 3 patients had interarterial course in coronary CT and had the slit-like orifice in coronary angiography. Area stenosis measured by IVUS was significantly higher in those with significant FFR after dobutamine challenge (63.7짹5.4% vs. 37.1짹11.9%, p=0.001). Area stenosis in IVUS was significantly correlated with FFR (r=-0.738, p<0.001) after dobutamine challenge but not with baseline FFR (r=-0.415, p=0.069). 12 (38.7%) patients had compression with slit-like orifice in coronary angiography and among them only 3 (35%) patients had FFR ���0.80. 5 patients (25%) had area of stenosis more than 50% and among them 3 patients (60%) had FFR ���0.80. 9 patients was positive in non-invasive stress test, but none of them had FFR ���0.80 nor area stenosis ���50%. During a median follow-up of 2.5 years, 2 all cause mortality and 6 target lesion revascularization occurred among 297 patients. Conclusion: The measurement of FFR in anomalous origin of RCA from LCC suggests most of these lesions do not have functional significance and that anatomical evaluation is not accurate in the assessment of the functional significance of the lesion. The outcomes of these patients seem to be favorable during long-term follow-up.