AbstractSkeletal abnormalities in neurofibromatosis type 1 syndrome (NF1) are observed in ∼50% of patients. Here, we describe the phenotype of Nf1Ocl mouse model with Nf1‐deficient osteoclasts. Nf1Ocl mice with Nf1+/− or Nf1−/− osteoclasts in otherwise Nf1+/+ background were successfully generated by mating parental Nf1flox/flox and TRAP‐Cre mice. Contrary to our original hypothesis, osteoporotic or fragile bone phenotype was not observed. The µCT analysis revealed that tibial bone marrow cavity, trabecular tissue volume, and the perimeter of cortical bone were smaller in Nf1 mice compared to Nf1 control mice. Nf1 mice also a displayed narrowed growth plate in the proximal tibia. In vitro analysis showed increased bone resorption capacity and cytoskeletal changes including irregular cell shape and abnormal actin ring formation in Nf1−/− osteoclasts. Surprisingly, the size of spleen in Nf1 mice was two times larger than in controls and histomorphometric analysis showed splenic megakaryocytosis. In summary, Nf1Ocl mouse model presented with a mild but specific bone phenotype. This study shows that NF1‐deficiency in osteoclasts may have a role in the development of NF1‐related skeletal abnormalities, but Nf1‐deficiency in osteoclasts in Nf1+/+ background is not sufficient to induce skeletal abnormalities analogous to those observed in patients with NF1. J. Cell. Biochem. 113: 2136–2146, 2012. © 2012 Wiley Periodicals, Inc.