Studies were conducted which examined urinary excretion and papillary production of cyclic-AMP in the rat following vasopressin (ADH) stimulation in the presence or absence of inorganic fluoride ion (F). In one set of experiments, six anesthetized Fischer 344 rats were administered 5 munits arginine vasopressin during iv saline and sodium fluoride (NaF) infusions. Urinary cyclic-AMP concentration was unchanged by ADH but declined during NaF infusion, while urinary cyclic-AMP excretion rate was unchanged by ADH or ADH NaF. In a second set of experiments, 30 rats were divided into six groups of 5 each, and renal papilla and cortex were analyzed for cyclic-AMP. Group I was decapitated and not otherwise surgically manipulated. A second group had iv saline for 90 min while a third group had iv saline and ADH. A fourth group had isotonic NaF iv for 90 min and a fifth group had NaF and ADH. The results indicate that papillary cyclic-AMP is significantly increased by both ADH and NaF doses which did not cause changes in urinary cyclic-AMP excretion rates. We conclude from these experiments that determination of urinary cyclic-AMP concentration is not the best measure of vasopressin action and that tubular sensitivity to the hormone in the presence of F was better demonstrated by changes in papillary cyclic-AMP concentration. Further, it appears that the site of the biochemical renal lesion caused by F is at a site beyond the generation of cyclic-AMP.