Mice that have been made deficient for the cystic fibrosis transmembrane conductance regulator (Cftr) usually die of intestinal obstruction. We have created Cftr-deficient mice and demonstrate prolonged survival among backcross and intercross progeny with different inbred strains, suggesting that modulation of disease severity is genetically determined. A genome scan showed that the major modifier locus maps near the centromere of mouse chromosome 7. Electrophysiological studies on mice with prolonged survival show that the partial rectification of Cl⁻ and Na⁺ ion transport abnormalities can be explained in part by up-regulation of a calcium-activated Cl⁻ conductance. Identification of modifier genes in our Cftr^m1HSC/Cftr^m1HSC mice should provide important insight into the heterogeneous disease presentation observed among CF patients.