Patients with familial hypertrophic cardiomyopathy (FHC) are at risk for ventricular arrhythmias and sudden death. Regional variability in the QT interval [QT dispersion (QTd)] is significantly increased in humans with FHC and ventricular arrhythmias. A mouse model of FHC resulting from a mutation in the alpha-myosin heavy-chain (Arg403Gln) was used to study the electrophysiologic phenotype of this disease. Cardiac electrophysiology studies and surface ECGs were performed in FHC mice and wild-type controls to evaluate the feasibility and significance of QTd measurements in predicting the risk for ventricular arrhythmias. Atrial and ventricular pacing electrodes were placed by either a transvenous or epicardial approach. Standard pacing and extrastimulus protocols were followed. The QT interval was measured in six surface ECG leads. QTd was defined as the difference between the maximum and minimum measured QT intervals. Male FHC mice had greater QTd than wild-type controls (37.1 +/- 3.0 ms versus 23.9 +/- 1.9 ms, p = 0.001). There was also a significant gender difference in QTd within each genotype; female wild-type mice had greater QTd than male wild-type mice (37.4 +/- 5.3 ms versus 23.9 +/- 1.9 ms, p = 0.005), and male FHC mice had greater QTd than female FHC mice (37.1 +/- 3.0 ms versus 27.2 +/- 2.0 ms, p = 0.02). Twelve of 23 FHC mice had inducible ventricular arrhythmias, whereas only 2 of 32 wild-type mice were inducible (p = 0.004). Although a significantly increased number of FHC mice had arrhythmias compared with wild-type mice, QTd did not correlate with arrhythmia inducibility. The importance of this study is that it validates the mouse model for further investigation of arrhythmogenic risk and gender differences in the electrophysiologic phenotype in FHC. It also suggests that although gender- and genotype-specific QTd values are increased, they do not predict arrhythmia risk in FHC mice.