Cholecystokinin (CCK) secreted from the duodenum during feeding has been shown to elicit satiety and stimulate growth of the pancreas in addition to affecting gastrointestinal function. In previous experiments hyperphagic Zucker obese rats were less sensitive to the effects of CCK on satiety and had a smaller pancreas than normal-weight rats. In the present experiments with hyperphagic lactating Zucker rats, the food intake response to exogenously administered CCK and the size and composition of the pancreas were measured. Food intakes after a 2-h fast were not decreased by 4.0 or 8.0 micrograms/kg CCK-8 during wk 1, 2, or 3 of lactation. However, in the same rats 2 wk after pups were weaned, 4.0 and 8.0 micrograms/kg CCK-8 decreased food intake 32% (2.1 +/- 0.4 vs. 3.1 +/- 0.3 g, paired t = 2.33, P less than 0.03) and 52% (1.5 +/- 0.2 vs. 3.1 +/- 0.5 g, paired t = 3.48, P less than 0.006). On day 18 of lactation, pancreas weight was increased 41% (1.38 +/- 0.05 vs. 0.98 +/- 0.02 g, paired t = 2.68, P less than 0.02) and contents of DNA, RNA, and protein were increased 57, 57, and 73%, respectively. Thus, hyperphagia in lactating female rats was associated with 1) decreased sensitivity to the satiety effect of CCK similar to that in hyperphagic obese rats and 2) hypertrophy of the pancreas in contrast to decreased pancreas size in obese rats.