Recent studies have established that mucosal butyrate stimulates electroneutral sodium-chloride (Na-C1) 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 ofbutyratedependent electroneutral Na-CI absorption. These studies were designed to examine butyrate-dependent electroneutral Na-C1 absorption in experimental conditions in which HCO3-dependent electroneutral Na-C1 absorption is inhibited: in Na-depleted (aldosteronetreated) animals and in the presence of increased mucosal cyclic adenosine monophosphate (AMP). Butyrate-dependent electroneutral Na-C1 absorption was markedly reduced in Na-depleted rats. In contrast, the inhibition of both net Na and net C1 absorption by 5 mM serosal theophylline was significantly less in butyrate-containing, HCO3-free Ringer solution than in butyrate-free-HCO3containing Ringer solution. These studies indicate that cyclic AMP does not inhibit butyrate-dependent electroneutral Na-C1 absorption and we propose that the mechanism of cyclic AMP inhibition of HCO3-dependent electroneutral Na-C1 absorption may be a result of its inhibition of C1-HCO3, not Na-H exchange.