Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic LQT1 and LQT2 rabbits that lack I_Ks or I_Kr currents, and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulae were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks I_Ks, prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks I_K1, prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both I_Ks and I_K1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block I_Kr, I_Ks, or I_K1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Conclusion: Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT-prolongation of anesthetic agents and their pro-arrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the pro-arrhythmic risk of I_Ks blockers in subjects with reduced I_Kr.