To evaluate the severity of hypertrophic cardiomyopathy (HCM) according to global, regional, and multi-layer longitudinal strain (LS) analysis using speckle-tracking echocardiography. From February 2007 to November 2014, we prospectively evaluated 375 consecutive HCM patients referred to our specialized cardiomyopathy center. Demographics, clinical, and rest and exercise echocardiographic parameters were collected according to a completely standardized protocol. Global, regional, and multilayer strain analyses were performed. Correlations between LS and other characteristics were evaluated, and we assessed their prognostic value to predict sudden cardiac death (SCD) or appropriate implantable cardioverter defibrillator (ICD) shocks during follow-up, using Cox proportional hazards analyses. We finally included 217 patients (50.1 ± 15.6 years, 67% male) but only 179 (82%) had LS analysis of sufficient quality. An inverse relation was observed between the mean basal left ventricular (LV) LS and diastolic parameters [E/Ea (r = − 0.30) and left atrium indexed volume (r = − 0.23)], as well as between the resting LV outflow-tract maximal gradient (r = − 0.26) or during peak exercise (r = − 0.20). Mean LS in the LV hypertrophic area was particularly related with maximal wall thickness (r = − 0.47) and transmural global LS with the degree of myocardial fibrosis in cardiac magnetic resonance (r = − 0.32). During a median follow-up of 2.8 ± 1.5 years, mean transmural LS in the hypertrophic area was predictor of SCD and appropriate ICD shock (10 events/179 patients, hazard ratio = 0.83 [95% CI 0.72–0.95], p = 0.01). Basal LS and hypertrophic area LS are valuable parameters to evaluate HCM severity. Mean hypertrophic area LS particularly seems predictive of SCD occurrence and appropriate ICD shocks.