Background: People with cystic fibrosis exhibit growth defects and brittle bones. That observation has been attributed, in part, to malnutrition and chronic pulmonary inflammation. We tested the hypothesis that disrup-tion of the cystic fibrosis transmembrane conductance regulator (Cftr) gene directly affects bone microarchitecture and integrity by studying bone of newborn Cftr-/- pigs. Methods: We examined femoral cortical and trabecular bones of Cftr-/- pigs less than 24 hours after birth using microcomputed tomography (mCT, Skyscan 1076, Bruker). Scans were performed with the following settings: tube voltage, 80 kV; tube current, 0.125 mA; and voxel size, 17 x 17 x 17 mm (x, y, z). Three-dimensional images were reconstructed and analysed using the NRecon GPU version and CTAn (Bruker) software programs, respectively. The cortical bone porosity and structure were defined using a 3.4 mm wide region centered on the middle of the femur. A total of 37 newborn Cftr-/- piglets (24 males and 13 females) and 18 newborn Cftr+/+ piglets (8 males and 10 females) was subjected to mCT scan. Results: Compared to newborn Cftr+/+ pig controls, Cftr-/- femoral bone exhibited significantly lower total volume (TV), bone volume (BV) and bone volume density (BV/TV) but only in females. However, the Cftr-/- bone mineral density (BMD) in trabecular and cortical tissues was signifi-cantly reduced in both sexes, compared to Cftr+/+ piglets. Interestingly, focusing at the porosity of cortical bone in Cftr-/- pigs as a determinant of bone fragility associated with high fracture risk, we observed higher closed porosity with a marked increase of closed pore surface in cortical bone of Cftr-/- pigs (+18.7% for males and +48% for females). These results suggest a lower bone remodelling, lower interconnectivity within the vascular network, and increased bone fragility in Cftr-/- animals. No significant difference was observed in the open cortical porosity, whatever the gender. Conclusion: Altogether, these data highlight the critical regulatory role of CFTR in bone development and maintenance, and suggest that some bone defects in people with cystic fibrosis are likely primary. Acknowledgment: This work was, in part, supported by the Associa-tion French Vaincre la Mucoviscidose.