Bone infections often become chronic and can be difficult to diagnose. In the present study, the osseous gene expression of several acute phase proteins (APPs) during osteomyelitis was investigated in a porcine model of implant associated osteomyelitis (IAO) (sampled 5, 10 and 15 days after infection) and in slaughter pigs with spontaneous hematogenous osteomyelitis, and compared to gene expression in liver tissue. Furthermore, immunohistochemical (IHC) staining of the APP complement component C3 (C3) was performed on the porcine osteomyelitis lesions together with material from human patients with chronic osteomyelitis. In the porcine bone samples a local upregulation of the expression of several APP genes, including serum amyloid A (SAA) and C3, was observed during infection. In the liver, only C-reactive protein (CRP) and Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 were significantly upregulated. Serum concentrations of CRP, SAA and haptoglobin were only upregulated at day 5 in infected animals of the IAO model. This indicates a limited systemic response to osteomyelitis. Similar numbers of positive IHC stained C3 leukocytes were found in human and porcine bone samples with chronic osteomyelitis, indicating a high transcriptional value of porcine models of osteomyelitis. The local upregulation of APPs could potentially be used for diagnosing osteomyelitis.