Apart from their pivotal role in the host defense against pathogens, leukocytes are also essential for bone repair, as fracture healing is initiated and directed by a physiological inflammatory response. Leukocytes infiltrate the fracture hematoma and produce several growth and differentiation factors that regulate essential downstream processes of fracture healing. Systemic inflammation alters the numbers and properties of circulating leukocytes, and we hypothesize that these changes are maintained in tissue leukocytes and will lead to impairment of fracture healing after major trauma. The underlying mechanisms will be discussed in this review.