Is it possible to identify most patients with hypertrophic cardiomyopathy (HCM) at risk of arrhythmic sudden cardiac death (SCD) and to prevent such events with prophylactic implantable cardioverter/defibrillators (ICDs)? In this cohort study of 2094 patients with HCM, ICD decision making was prospectively assessed based on conventional major risk markers derived from the literature and enhanced from 2011 American College of Cardiology/American Heart Association guidelines over a 17-year experience at a single HCM center. Rates of appropriate ICD therapy terminating potentially lethal ventricular tachyarrhythmias exceeded SCDs in patients without ICDs by almost 50-fold. A prospective individual risk factor strategy predicted SCD events in nearly all at-risk patients with HCM, resulting in prophylactically implanted ICDs that prevented arrhythmic SCD events. This cohort study assesses the reliability of sudden cardiac death prediction methods leading to prophylactic implantable cardioverter/defibrillator recommendations to reduce the number of sudden cardiac deaths occurring in patients with hypertrophic cardiomyopathy. Strategies for reliable selection of high-risk patients with hypertrophic cardiomyopathy (HCM) for prevention of sudden cardiac death (SCD) with implantable cardioverter/defibrillators (ICDs) are incompletely resolved. To assess the reliability of SCD prediction methods leading to prophylactic ICD recommendations to reduce the number of SCDs occurring in patients with HCM. In this observational longitudinal study, 2094 predominantly adult patients with HCM consecutively evaluated over 17 years in a large HCM clinical center were studied. All patients underwent prospective ICD decision making relying on individual major risk markers derived from the HCM literature and an enhanced American College of Cardiology/American Heart Association (ACC/AHA) guidelines–based risk factor algorithm with complete clinical outcome follow-up. Data were collected from June 2017 to February 2018, and data were analyzed from February to July 2018. Arrhythmic SCD or appropriate ICD intervention for ventricular tachycardia or ventricular fibrillation. Of the 2094 study patients, 1313 (62.7%) were male, and the mean (SD) age was 51 (17) years. Of 527 patients with primary prevention ICDs implanted based on 1 or more major risk markers, 82 (15.6%) experienced device therapy–terminated ventricular tachycardia or ventricular fibrillation episodes, which exceeded the 5 HCM-related SCDs occurring among 1567 patients without ICDs (0.3%), including 2 who declined device therapy, by 49-fold (95% CI, 20-119; P = .001). Cumulative 5-year probability of an appropriate ICD intervention was 10.5% (95% CI, 8.0-13.5). The enhanced ACC/AHA clinical risk factor strategy was highly sensitive for predicting SCD events (range, 87%-95%) but less specific for identifying patients without SCD events (78%). The C statistic calculated for enhanced ACC/AHA guidelines was 0.81 (95% CI, 0.77-0.85), demonstrating good discrimination between patients who did or did not experience an SCD event. Compared with enhanced ACC/AHA risk factors, the European Society of Cardiology risk score retrospectively applied to the study patients was much less sensitive than the ACC/AHA criteria (34% [95% CI, 22-44] vs 95% [95% CI, 89-99]), consistent with recognizing fewer high-risk patients. A systematic enhanced ACC/AHA guideline and practice-based risk factor strategy prospectively predicted SCD events in nearly all at-risk patients with HCM, resulting in prophylactically implanted ICDs that prevented many catastrophic arrhythmic events in this at-risk population.