Recent studies have established that mucosal butyrate stimulates electroneutral sodium-chloride (NaCl) absorption in the distal colon of the rat and a model in which Na-hydrogen (H) and Cl-butyrate exchanges are coupled has been proposed as the mechanism of butyrate-dependent electroneutral Na-Cl absorption. These studies were designed to examine butyrate-dependent electroneutral Na-Cl absorption in experimental conditions in which HCO₃-dependent electroneutral Na-Cl absorption is inhibited: in Na-depleted (aldosterone-treated) animals and in the presence of increased mucosal cyclic adenosine monophosphate (AMP). Butyrate-dependent electroneutral Na-Cl absorption was markedly reduced in Na-depleted rats. In contrast, the inhibition of both net Na and net Cl absorption by 5 mM serosal theophylline was significantly less in butyrate-containing, HCO₃-free Ringer solution than in butyrate-free-HCO₃-containing Ringer solution. These studies indicate that cyclic AMP does not inhibit butyrate-dependent electroneutral Na-Cl absorption and we propose that the mechanism of cyclic AMP inhibition of HCO₃-dependent electroneutral Na-Cl absorption may be a result of its inhibition of Cl-HCO₃, not Na-H exchange.