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T he mechanisms underlying mucus-associated pathologies in cystic fibrosis (CF) remain obscure. However, recent studies indicate that CF transmembrane conductance regulator (CFTR) is required for bicarbonate (HCO₃^–) transport and that HCO₃^– is critical for normal mucus formation. We therefore investigated the role of HCO₃^– in mucus secretion using mouse small intestine segments ex vivo. Basal rates of mucus release in the presence or absence of HCO₃^– were similar. However, in the absence of HCO₃^–, mucus release stimulated by either PGE₂ or 5-hydroxytryptamine (5-HT) was approximately half that stimulated by these molecules in the presence of HCO₃^–. Inhibition of HCO₃^– and fluid transport markedly reduced stimulated mucus release. However, neither absence of HCO₃^– nor inhibition of HCO₃^– transport affected fluid secretion rates, indicating that the effect of HCO₃^– removal on mucus release was not due to decreased fluid secretion. In a mouse model of CF (mice homozygous for the most common human CFTR mutation), intestinal mucus release was minimal when stimulated with either PGE₂ or 5-HT in the presence or absence of HCO₃^–. These data suggest that normal mucus release requires concurrent HCO₃^– secretion and that the characteristically aggregated mucus observed in mucin-secreting organs in individuals with CF may be a consequence of defective HCO₃^– transport.