Objectives: Myeloid p38 alpha/MAPK regulate and coordinate osteoclastogenesis. The present study was conducted to investigate the role of myeloid p38 alpha/MAPK during orthodontic tooth movement. Methods: Orthodontic tooth movement was performed in wildtype and p38 alpha(Delta myel) mice lacking p38 alpha/MAPK expression in myeloid cells. First, bone parameter as well as osteoblast and osteoclast number were determined in tibiae. RNA was isolated from the untreated and orthodontically treated maxillary jaw side and expression of genes involved in inflammation and bone remodelling were analysed. Finally, periodontal bone loss, alveolar bone density and extent of orthodontic tooth movement were assessed. Results: Bone density was increased in p38 alpha(Delta myel) mice compared to wildtype mice in tibiae (p = 0.043) and alveolar bone (p = 0.003). This was accompanied by a reduced osteoclast number in tibiae (p = 0.005) and TRAP5b in serum (p = 0.015). Accordingly, expression of osteoclast-specific genes was reduced in p38 alpha(Delta myel) mice. Extent of tooth movement was reduced in p38 alpha(Delta myel) mice (p = 0.024). This may be due to the higher bone density of the p38 alpha Delta myel mice. Conclusions: Myeloid p38 alpha/MAPK thus appears to play a regulatory role during orthodontic tooth movement by regulating osteoclastogenesis.