Twenty-nine consecutive patients with symptomatic hypertrophic cardiomyopathy and a mean age of 44.8 +/- 12.2 years (range 21 to 63) underwent complex invasive and noninvasive testing to identify a risk profile for syncope. Clinical, morphologic, electrophysiologic and hemodynamic variables at rest and at a symptom-limited pacing rate were analyzed for a significant association with syncope. Exact stepwise logistic regression analysis identified three variables as significant independent predictors of syncope in hypertrophic cardiomyopathy: 1) age less than 30 years (beta = 4.803; p = 0.0007); 2) left ventricular end-diastolic volume index less than 60 ml/m2 (beta = 3.302; p = 0.006); and 3) nonsustained ventricular tachycardia on 72 h ambulatory electrocardiographic monitoring (beta = 2.5909; p = 0.03). The combined occurrence of all three variables had a sensitivity and specificity of 100% in identifying eight patients with syncopal events. Thus, the risk for syncope in hypertrophic cardiomyopathy is high in young patients with the combination of low left ventricular filling volume and episodes of nonsustained ventricular tachycardia. This finding might also explain the mechanism of syncope in hypertrophic cardiomyopathy as low input-low output failure induced by a sudden increase in heart rate in the presence of a low filling volume.