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Background: Four voltage-gated potassium currents, I to,f (KV4.2), I to,s (KV1.4), I K,slow (KV1.5+KV2.1), and I SS (TASK1), govern murine ventricular repolarization. Although the accessory subunit KChIP2 influences I to,f expression, in preliminary experiments we found that action potential duration (APD) is maintained in KChIP2 knockout mice. Objective: We tested the role of KChIP2 in regulating APD and studied the underlying ionic currents. Methods: We used microelectrode techniques, whole-cell patch clamp studies, and real-time polymerase chain reaction amplification to characterize ventricular repolarization and its determinants in wild-type and KChIP2−/− mice. Results: Despite comparable baseline action potentials, APD was more markedly prolonged by 4-aminopyridine (4-AP) in KChIP2−/− preparations. Peak K+ current densities were similar in wild-type and KChIP2−/− cells (mean ± SEM I P: 28.3 ± 2 (n = 27) vs. 29.2 ± 2 pA/pF (n = 24), respectively; P > .05). Heteropodatoxin-2 (HpTx-2, 1 μM) had no effect on current amplitude in KChIP2−/− myocytes. The current fractions sensitive to 4-AP (50 μM and 1 mM) were larger in KChIP2−/− than wild-type (P < .05). Real-time polymerase chain reaction showed absence of KChIP2 and increased KV1.5 expression in KChIP2−/− ventricular myocardium. Conclusion: KChIP2 deficiency eliminated HpTx-2-sensitive I to,f, but had little impact on total APD, secondary to upregulation of 4-AP-sensitive I K,slow in association with increased KV1.5 expression. There is increased sensitivity to 4-AP-mediated APD prolongation in KChIP2−/−. Thus, KChIP2 seems important for murine repolarization in circumstances of reduced repolarization reserve. [Copyright &y& Elsevier]