Objectives: The relation of indirect vasodilator use to cardiac events (CE) is undefined for chronic severe nonischemic mitral regurgitation (MR). The aim of this study was to resolve this knowledge deficiency. Methods: Data from 52 consecutive patients in our prospective natural history study with isolated chronic severe nonischemic MR were assessed post hoc over 19 years to examine the relation of indirect vasodilator use to subsequent CE (death or indications for valve surgery). At entry, no patient had surgical indications, 14% had hypertension (HTN) and 7 chronically received vasodilators (5 angiotensin-converting enzyme inhibitor, 1 receptor blocker and 1 α-adrenergic blocker). CE differences were assessed by log-rank comparison of Kaplan-Meier curves. Results: During follow-up, CE included sudden death (1 patient), heart failure (7 patients), atrial fibrillation (6 patients), left ventricular (LV) systolic dimension >4.5 cm (12 patients), LV ejection fraction (EF) <60% (7 patients), right ventricular EF <35% (2 patients) and combination CE (7 patients). Overall, vasodilator use did not predict CE (not significant). However, patients without HTN had higher CE rates with vasodilators than without (p = 0.007), while those with HTN and vasodilators had lower CE rates than those without vasodilators (p = 0.04). Conclusion: Vasodilator use appears to confer no survival benefit in patients with chronic severe MR. The small number of patients with HTN precludes conclusions about modulation of vasodilator effect by HTN. Randomized trials are needed to conclusively evaluate this association.