The human ether-a-go-go related gene (HERG) encodes K+ channel identified as a molecular target for mutations underlying some forms of the long Q-T syndrome, a lethal cardiac arrhythmia. Recent studies revealed that HERG is abundantly expressed in a variety of tumor cells. Yet, the role of HERG in tumor cells had remained unclear. Here, we show that HERG conductance markedly promotes H2O2-induced apoptosis of various tumor cells, whereas HERG expression facilitates the tumor cell proliferation caused by tumor necrosis factor (TNF) ligand (TNF-alpha). Immunostaining and immunocoprecipitation reveal coexpression of HERG and TNF receptor 1 on the cytoplasmic membrane, which is correlated with greater activities of nuclear transcription factor, nuclear factor-kappaB, in HERG-expressing tumor cells. Our data suggest that HERG K+ channel is a regulator of tumor cell proliferation and apoptosis and provide a potential new target for cancer therapy.