Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development. We demonstrate that mast cell infiltration is dependent on SCF from tumor Schwann cells. However, removal of mast cells by depleting the main SCF source only slightly affects neurofibroma progression. Other inflammation signatures show that all neurofibromas are associated with high levels of macrophages regardless of Scf status. These findings suggest an active inflammation in neurofibromas and partly explain why mast cell removal alone is not sufficient to relieve tumor burden in this experimental neurofibroma model. Furthermore, we show that plexiform neurofibromas are highly associated with injury-prone spinal nerves that are close to flexible vertebras. In summary, our study details the role of inflammation in neurofibromagenesis. Our data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored.