We conducted a literature review to determine which laboratory investigations are useful for the ED evaluation of osteomyelitis. Thirty-six relevant papers were identified. We concluded that in adult and paediatric patients with a clinically low level of suspicion of osteomyelitis, an age-adjusted normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) <5 mg/L should reassure the clinician that no further urgent investigation is required. For patients with risk factors for osteomyelitis or a clinically high level of suspicion, a normal ESR or CRP <5 mg/L should not rule out the diagnosis of osteomyelitis, especially in patients with puncture wounds or foot ulcers/infections. In patients with any suspicion of osteomyelitis and otherwise unexplained ESR >30 mm/h and/or CRP >10–30 mg/L further definitive investigation is required. The white blood count is not helpful in the evaluation of osteomyelitis.