Mouse models of cystic fibrosis that are generated by targeted disruption (knockout) of the cystic fibrosis transmembrane conductance regulator gene, cftr(-/-), typically die shortly after weaning, from intestinal obstruction/rupture caused by an inability to secrete fluid into the bowel lumen. We investigated the use of a commercial osmotic laxative, Colyte, provided continuously in the drinking water, to increase the survival of cftr(-/-) mice. Genotype analysis of 623 offspring surviving at 10 days of age yielded 28.1% cftr(+/+), 59.6% cftr(+/-), and 12.4% cftr(-/-) mice (25% predicted), suggesting that cftr(-/-) mice have a significant perinatal mortality rate. However, of the 77 cftr(-/-) mice alive at 10 days of age, >98% survived weaning and were maintained in apparent health to a minimum of 56 days of age (arbitrary age for experimentation). In intestinal bioelectric studies Colyte-treated drinking water, compared with tap water, had no significant effect on basal short-circuit current, cyclic AMP-stimulated Cl- secretion, Na+-coupled glucose absorption, or electrogenic Na+ absorption across intestinal sections from cftr(+/+ or +/-) mice. Other than a mild dilatation of the distal portion of the colon in the Colyte-treated animals, examination of jejunal and colonic sections revealed no histologic differences between the two treatments. These findings indicate that the chronic use of Colyte osmotic laxative in drinking water is an economical means of greatly increasing the survival of CFTR knockout mice without altering the major electrolyte transport processes or histomorphologic integrity of the intestine.