J waves in inferolateral leads are associated with an increased risk for idiopathic ventricular fibrillation. The mechanism behind such J waves is unknown. A similarity with Brugada syndrome (BS) exists but while administration of sodium (Na) channel blockers increases J waves in BS it attenuates inferolateral J waves. We hypothesized that regionally reduced conduction velocity in the lateral wall can explain both inferolateral J waves and their attenuation by Na-channel blockers. METHODS The effects of Na-channel block, reduced coupling, and increased transient outward current were evaluated with computer simulations using a detailed model of the human heart and torso. As far as possible findings were backed up with experiments in explanted pig hearts. RESULTS Reduced Na current in lateral but not in other regions induced inferolateral J waves. Increased transient outward current and cellular uncoupling caused only subthreshold J-point elevations. Administration of Na-channel blockers deformed and prolonged the QRS complex, masking the inferolateral J waves. CONCLUSION Regionally reduced Na current can explain inferolateral J waves. The fact that the lateral region is normally late-activated is crucial for the development of J waves and may explain the special importance of the inferolateral leads. The proposed mechanism also explains attenuation of J waves by Na-channel blockers.