Keratinocytes are important for epithelial antimicrobial barrier function. The activity of ion channels can affect the proliferation of keratinocytes. Little is known about Ca2+-activated K+ currents in these cells. Ion currents in normal human oral keratinocytes were characterized with a patch-clamp technique. In whole-cell configuration, depolarizing pulses evoked K+ outward currents ( I K) in oral keratinocytes. Iberiotoxin (200 nM) and paxilline (1 μM) suppressed I K; however, neither apamin (200 nM) nor 5-hydroxydecanoate (30 μM) had any effects on it. Caffeic acid phenethyl ester, a compound of honeybee propolis, increased I K with an EC50 value of 12.8 ± 1.2 μM. In inside-out patches, a BKCa channel was observed in keratinocytes, but not in oral squamous carcinoma (OCE-M1) cells. Caffeic acid phenethyl ester or cinnamyl-3,4-dihydroxy-α-cyanocinnamate applied to the intracellular surface of a detached patch increased BKCa-channel activity. The results demonstrate that the properties of BKCa channels in normal human oral keratinocytes are similar to those described in other types of cells. Caffeic acid derivatives can also stimulate BKCa-channel activity directly.