Abstract: The aim of this study was to investigate the effects of phloretin on the Ca2+-activated K+ channel with large conductance (BKCa) and to assess a possible contribution of the BKCa to phloretin-induced changes of endothelial proliferation and Nitric Oxide (NO) production. In this study the patch-clamp technique was used to perform single channel recordings of the BKCa in cultured endothelial cells derived from Human Umbilical Cord Veins (HUVEC). BKCa open state probability (NPo) was significantly increased after 5 min of continuous perfusion with 80 μmol L -1 phloretin (14 fold increase at a pipette potential of 100 mV; n=31, p<0.05). NPo was not increased by phloretin if cells were simultaneously incubated with the highly selective BKCa-inhibitor iberiotoxin (100 nmol L -1). The production of NO was examined using a cGMP-radio-immuno-assay. Phloretin caused a significant increase of acetylcholine-induced cGMP-levels from 303.1±31.1 fmol/well (acetylcholine; 1 μmol L -1) to 568.4±76.1 fmol/well (acetylcholine + phloretin; 80 μmol L -1), that was significantly reduced if iberiotoxin (100 nmol L -1) was added (n=9; p<0.01). Endothelial proliferation was significantly reduced by phloretin (-70.6%, n=12, p<0.01, cell counts; -86.5%, n=20, p<0.01, [3H]-thymidine-incorporation). This effect of phloretin was independent of BKCa-activity, because it was not changed by the addition of iberiotoxin. In conclusion the results of this study demonstrated, that phloretin activates the endothelial BKCa, which causes an increase of cGMP-levels. Furthermore, the proliferation of HUVEC is decreased by phloretin. The described findings might help to understand why flavanoids like phloretin have beneficial effects in the protection against atherosclerosis.