The influence of left ventricular outflow tract obstruction on the clinical outcome of hypertrophic cardiomyopathy remains unresolved. We assessed the effect of outflow tract obstruction on morbidity and mortality in a large cohort of patients with hypertrophic cardiomyopathy who were followed for a mean (+/-SD) of 6.3+/-6.2 years. Of the 1101 consecutive patients, 273 (25 percent) had obstruction of left ventricular outflow under basal (resting) conditions with a peak instantaneous gradient of at least 30 mm Hg. A total of 127 patients (12 percent) died of hypertrophic cardiomyopathy, and 216 surviving patients (20 percent) had severe, disabling symptoms of progressive heart failure (New York Heart Association NYHA functional class III or IV). The overall probability of death related to hypertrophic cardiomyopathy was significantly greater among patients with outflow tract obstruction than among those without obstruction (relative risk, 2.0; P=0.001). The risk of progression to NYHA class III or IV or death specifically from heart failure or stroke was also greater among patients with obstruction (relative risk, 4.4; P<0.001), particularly among patients 40 years of age or older (P<0.001). Age-adjusted multivariate analysis confirmed that outflow tract obstruction was independently associated with an increased risk of both death related to hypertrophic cardiomyopathy (relative risk, 1.6; P=0.02) and progression to NYHA class III or IV or death from heart failure or stroke (relative risk, 2.7; P<0.001). The likelihood of severe symptoms and death related to outflow tract obstruction did not increase as the gradient increased above the threshold of 30 mm Hg. In patients with hypertrophic cardiomyopathy, left ventricular outflow tract obstruction at rest is a strong, independent predictor of progression to severe symptoms of heart failure and of death.