Cholecystokinin (CCK) released postprandially from duodenum is an interesting potential stimulus of small intestinal secretion. We have compared effects of CCK on duodenal bicarbonate secretion and enterocyte intracellular calcium ([Ca²⁺]_i) signaling. Methods in vivo: Lewis x Dark Agouti rats were either fasted overnight or had continuous access to food. Animals were anaesthetized (Inactin) and proximal duodenum cannulated in situ. Mucosal bicarbonate secretion (pH stat) and mean arterial blood pressure were continuously recorded. CCK-8 was administered intra-arterially close to the duodenum. In vitro: Pieces of duodenal mucosa were exposed to mild digestion (collagenase/dispase) to yield clusters (10– 100 cells) of enterocytes. After loading with fura-2 and mounting in a perfusion chamber, [Ca²⁺]_i was measured with fluorescence imaging. Results: Low doses of CCK-8 (3–60 pmol/kg,h) induce a dose-dependent rise in duodenal bicarbonate secretion. With all doses and despite continuous infusion, the response was transient in nature and started to decline after 10 min. Findings in fasted and continuously fed animals were similar and the CCK_A-antagonist devazepide (0.5 mol/ kg, i.v.) inhibited the rise in secretion. Superfusion with CCK-8 (1–50 nmol/L) induced enterocyte [Ca²⁺]_isignaling. After an initial peak response, [Ca²⁺]_i returned to basal or near basal values within 3–5 min. Further, repetitive exposures to CCK rapidly down-regulated the response. As in vivo, devazepide (100 nmol/L) prevented the response to CCK-8. Conclusions: Low doses of CCK induce intracellular [Ca²⁺]_i signaling and stimulation of duodenal alkaline secretion by an action at CCK_A-receptors. Postprandial release of CCK may contribute to duodenal protection against acid discharged from the stomach.