The present study aims to determine the influence of microvascular dysfunction (MVD) in the prognosis of patients presenting isolated left bundle branch block (LBBB). Methods: We studied 30 patients (pts), 22 males, 8 females, mean age 57 ± 4 years, with isolated LBBB, with a mean follow up of 48 ± 6 months. The control group consisted of 20 healthy individuals, 12 males, mean age 52 ± 10 years. Both groups were screened for cardiovascular risk factors (RF); they also had an echocardiogram and Coronary CT Scan, ruling out both structural heart disease and obstructive lesions of the epicardial coronary arteries. A myocardial perfusion study was then performed, with two groups emerging according to these results: Group A, 8 pts (26%), with reversible perfusion defects, in which the diagnosis of MVD was suspected, and Group B, 22 pts (74%), with either normal perfusion or minor septal/apical reversible defects (related to LBBB). All Group A pts, and 9 of the Group B pts, underwent coronary arteriography, with intracoronary acetylcholine and nitroglycerine infusion, thus evaluating vasomotor response as endothelium dependent (acetylcholine) or endothelium independent (nitroglycerine). During follow up, we reviewed functional class, 12 lead ECG and echocardiogram on a yearly basis. Results: All Group A patients had an abnormal acetylcholine response; only three of them had abnormal response to nitroglycerine infusion, suggesting endothelium dependent MVD. Of those in Group B, only one patient had abnormal acetylcholine response. At the end of the follow up period, 3 pts (37%) in Group A, showed functional class decrease vs 5 pts (22%) of those in Group B. In Group A, a significant increase of End Diastolic Left Ventricle Diameter (EDLVD) was found (51.6 ± 3.6 vs 59.3 ± 6.8 mm; p variation. In neither group major complications (death, heart failure admissions) were found. Conclusion: We confirm the association between MVD and a worse clinical prognosis in isolated LBBB patients. Repeated ischemia and myocardial fibrosis are highlighted as possible physiopathological mechanisms, precluding a progressive left ventricular function decrease, with a higher mortality and arrhythmia risk. Endothelial function preserving strategies, both preventive and therapeutic, might be useful in improving LBBB with MVD patient’s prognosis.