Some cystic fibrosis transmembrane conductance regulator (CFTR) mutations, such as G551D, result in a correctly localized Cl⁻ channel at the cell apical membrane, albeit with markedly reduced function. Patch-clamp studies have indicated that both phosphatase inhibitors and 3-isobutyl-1-methylxanthine (IBMX) can induce Cl⁻ secretion through the G551D mutant protein. We have now assessed whether these agents can induce Cl⁻ secretion incftr^G551D mutant mice. No induction of Cl⁻secretion was seen with the alkaline phosphatase inhibitors bromotetramisole or levamisole in either the respiratory or intestinal tracts of wild-type orcftr^G551D mice. In contrast, in G551D intestinal tissues, IBMX was able to produce a small CFTR-related secretory response [means ± SE: jejunum, 1.8 ± 0.9 μA/cm²,n = 7; cecum, 3.7 ± 0.8 μA/cm²,n = 7; rectum (in vivo), 1.9 ± 0.9 mV, n = 5]. This was approximately one order of magnitude less than the wild-type response to this agent and, in the cecum, was significantly greater than that seen in null mice (cftr^UNC ). In the trachea, IBMX produced a transient Cl⁻ secretory response (37.3 ± 14.7 μA/cm²,n = 6) of a magnitude similar to that seen in wild-type mice (33.7 ± 4.7 μA/cm²,n = 9). This response was also present in null mice and therefore is likely to be independent of CFTR. No effect of IBMX on Cl⁻secretion was seen in the nasal epithelium ofcftr^G551D mice. We conclude that IBMX is able to induce detectable levels of CFTR-related Cl⁻ secretion in the intestinal tract but not the respiratory tract through the G551D mutant protein.