OBJECTIVE We report cases of central or atypical skull base osteomyelitis and review issues related to the diagnosis and treatment. METHODS The four cases presented, which were drawn from the Oxford, United Kingdom, skull base pathology database, had a diagnosis of central skull base osteomyelitis. RESULTS Four cases are presented in which central skull base osteomyelitis was diagnosed. Contrary to malignant otitis externa, our cases were not preceded by immediate external infections and had normal external ear examinations. They presented with headache and a variety of cranial neuropathies. Imaging demonstrated bone destruction, and subsequent microbiological analysis diagnosed infection and prompted prolonged antibiotic treatment. CONCLUSIONS We concluded that in the diabetic or immunocompromised patient, a scenario of headache, cranial neuropathy, and bony destruction on imaging should raise the possibility of skull base osteomyelitis, even in the absence of an obvious infective source. The primary goal should still be to exclude an underlying malignant cause.