5-Hydroxytryptamine (5-HT) increases short-circuit current when added to the serosal side of human isolated ileal mucosa; mucosally applied 5-HT was ineffective. Tetrodotoxin reduced both basal short-circuit current and increases in short-circuit current due to electrical field stimulation of mucosal nerves. However, neither tetrodotoxin, ondansetron nor methysergide plus ketanserin affected 5-HT induced increases in short-circuit current. Application of SDZ 205-557 (2-diethylaminoethyl-(2-methoxy-4-amino-5-chloro) benzoate) to the tissue caused a significant increase in the concentration ratio between two successive 5-HT response curves. It is concluded that the effect of 5-HT on short-circuit current of human ileal mucosa appears to be due to stimulation of a 5-HT4 receptor.