Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current (I-to) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I-to and that its overexpression might specifically alter PF I-to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I-to. Methods and Results: Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and ventricular muscle I-to had similar density, but PF I-to differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I-to density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K+-channel interacti Conclusions: These results point to a previously unknown central role of DPP6 in PF I-to, with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation.