Aims: Heme, the prosthetic group present in many heme proteins such as hemoglobin, also serves as a signaling molecule, modulating a variety of proteins including select ion channels. Here we examined to what degree heme acutely modulates voltage-gated Kv2.1 channels. These proteins are abundantly expressed, playing a role in neurons, cardiac tissue and in insulin-secreting beta cells of the pancreas. Methods: Rat and human Kv2.1 channels were expressed in Xenopus oocytes and HEK 293 cells. The effects of hemin and related porphyrins were studied in patch-clamp experiments employing the inside-out and whole-cell recording configurations. Results: Hemin (200 nM) was without effect on the amplitude and kinetics of Kv2.1 channels when applied to the extracellular side. Application of hemin to the cytosolic side of the membrane, however, profoundly altered the gating kinetics of the channel. Under physiological ion conditions, 200 nM hemin had a biphasic effect on current amplitude: a rapid increase in current by about 100% was followed by a gradual decline. Additionally, activation kinetics slowed and the voltage dependence of activation shifted to the right. Recordings in symmetrical high K+ conditions unmasked rapid inactivation of Kv2.1 channels termed U-type (Immke et. al. 1999). This inactivation was potently removed by hemin (half-maximal concentration lower than 50 nM), resulting in substantial increase in current amplitude. Protoporphyrin IX and Fe²⁺ were without effect. Conclusion: Intracellular hemin is a strong activator of Kv2.1 channel. Although the effects on current kinetics are multi-facetted, the major impact appears to be removal of inactivation. Thus, heme/hemin may be a suited tool for studying the mechanism of U-type inactivation of Kv2.1 channels. Moreover, this study shows that fluctuations in intracellular heme concentration may affect cellular excitability by means of regulating Kv2.1 activity.