In agreement with previous reports, we found that absence of K+from the serosal bath of the toad urinary bladder substantially impairs vasopressin and cAMP‐stimulated water flow. The decreased response to vasopressin appears unrelated to prostaglandin production since inhibition of endogenous prostaglandins by pretreatment with naproxen 10−5M failed to prevent the effect seen with K+‐free Ringer's. The resistance to vasopressin does not appear to be directly related to epithelial K+concentrations, in that maneuvers leading to decreased intracellular K+failed to produce a similar effect. A more likely explanation appears to be that K+‐free Ringer's induces an increased cytosolic Ca++which, in turn, decreases the hydrosmotic effects of vasopressin. Several lines of evidence argue in favor of such an explanation: (a) Increased cytosolic Ca++had been found in other tissues with low extracellular K+; (b) The resistance to vasopressin decreases with decreased serosal Ca++; (c) The effects of K+‐free Ringer's are not additive in situations believed to have increased epithelial Ca++,i.e.replacement of serosal Na+with choline; (d) The effects of K+‐free serosal bathing medium could be both prevented and/or reversed if already established by increasing serosal bath, and presumably intracellular, pH, which is believed to decrease intrace