Histamine increased the transmural potential difference across rat colon in‐vivo and induced a net secretion of fluid. Both effects were inhibited by indomethacin. Histamine increased the potential difference and short‐circuit current, and reduced tissue resistance in colonic sheets in‐vitro. This response was reduced in the absence of chloride in the bathing medium or in the presence of serosal frusemide, suggesting that histamine stimulated electrogenic chloride secretion by the colon. The rise in short‐circuit current induced by histamine was calcium‐dependent since it was reduced in the absence of serosal calcium or in the presence of serosal verapamil. Indomethacin, a cyclo‐oxygenase inhibitor, and mepacrine, a phospholipase inhibitor, both caused a dose‐dependent inhibition of the electrical response of colonic sheets to histamine, without affecting the rise in short‐circuit current induced by prostaglandin E₂. The stimulation of chloride secretion induced by histamine in rat colon therefore appears to be mediated by an increased production of prostaglandins.