Rationale: A loss of function mutation in the Cystic Fibrosis Transmembrane Conductance Regulator gene is believed to be an independent risk factor for bone disease in patients with cystic fibrosis. Objectives: The objective of this work was to use congenic mice as a pre-clinical model to examine the bone phenotype of Cftr ^-/- mice and Control littermates at 8, 12 and 28 weeks of age. Methods: The bone phenotype of Control and Cftr^-/- mice was evaluated using quantitative imaging, histologic and histomorphometric analyses and serum levels of bone biomarkers. Measurements and Main Results: At 12 weeks of age, Cftr ^-/- mice were smaller, had lower bone mineral density, cortical bone thinning, and altered trabecular architecture compared with Cftr^+/+ or Cftr^+/- Control mice. In skeletally mature 28 week old mice, there were persistent deficits in cortical and trabecular bone structure in Cftr^-/- mice despite significant, quantifiable improvements. Cftr^-/- mice also had lower serum insulin like growth factor 1 levels at 12 weeks of age than did Control mice, while parathyroid hormone and 25-hydroxy vitamin D levels were not significantly different. Conclusions: Persistent osteopenia and structural abnormalities in adult Cftr^-/- mice, in the absence of overt respiratory and gastro-intestinal disease, suggests that loss of Cftr function has a direct impact on bone metabolism in Cftr^-/- mice that is not gender specific nor subject to haplotype insufficiency.