Abstract Background Exercise echocardiography (ExE) may assess left ventricular (LV) systolic and diastolic function, LV outflow tract (LVOT) obstruction and mitral regurgitation (MR). We aimed to assess the feasibility and prognostic value of the assessment of all these issues during exercise in patients with hypertrophic cardiomyopathy (HCM). Methods LV systolic and diastolic function, LVOT gradients, and MR were evaluated during ExE in 285 patients with HCM (age 60±14 years, 168 men) and preserved LVEF (≥50%). Recordings were obtained at rest and peak exercise for regional/global LV systolic function and at rest and within 1.5 min after exercise for the rest of assessments: LVOT gradients, MR and ratio of early LV inflow velocity to early tissue Doppler septal annulus velocity (E/e'). Results Feasibility was 100%, 97%, 98% and 98% for LV systolic function, E/e', LVOT gradients, and MR assessments at exercise, respectively. Thirty-seven patients (13%) had LVOT obstruction at rest, and 76 (27%) developed exercise-induced LVOT obstruction. Mean resting LVEF was 63±3%. New wall motion abnormalities (WMAs) were detected in 38 patients (13%). E/e'>15 was observed in 108 patients at rest (38%) and in 119 at exercise (42%). Corresponding figures for significant MR (moderate or severe) were 20 (7%) and 17 (6%). During follow-up of 3.9±2.5 years, 21 patients had a hard event (cardiac death or transplantation, appropriate discharge of a defibrillator, stroke, myocardial infarction, hospitalization for heart failure), 33 a combined event (hard plus new atrial fibrillation or syncope), and 53 a combined event plus any interventionism. After adjustment, LV wall thickness, resting LVEF, maximal workload in Metabolic Equivalents (METs), and E/e' post-exercise resulted independent predictors of hard events (HR=1.45, 95% CI: 1.21–1.74, p<0.001; HR=0.80, CI: 0.71–0.89, p<0.001; HR=0.73, 95% CI: 0.62–0.86, p<0.001; HR=1.08, 95% CI: 1.02–1.14, p<0.009, respectively). Independent predictors of combined events included also LV wall thickness, resting LVEF, and METs, along with therapy with beta-blockers at the time of ExE (HR=1.29, 95% CI: 1.12–1.50, p=0.001; HR=0.89, CI: 0.81–0.97, p=0.012; HR=0.83, 95% CI: 0.74–0.93, p=0.001; HR=2.51, 95% CI: 1.20–5.25, p=0.015), whereas the model for combined events+any interventionism consisted of beta-blockers, LV wall thickness, LA dimension, METs and new WMAs. (HR=2.15, 95% CI: 1.20–3.86, p=0.01; HR=1.17, 95% CI: 1.03–1.32, p=0.02; HR=1.07, CI: 1.02–1.11, p=0.005; HR=0.90, 95% CI: 0.82–0.98, p=0.01; HR=2.33, 95% CI: 1.17–4.63, p=0.016) Conclusions A comprehensive assessment during ExE is feasible for patients with HCM and provides significant incremental prognostic information Funding Acknowledgement Type of funding source: None