Skull base osteomyelitis (SBO) is an infection of the temporal, sphenoid, or occipital bone that can be a challenge to diagnose because of its nonspecific symptoms, long clinical course, and radiologic findings that mimic those of other entities. The authors review this unusual infection on the basis of six proven cases. The diagnosis of SBO should be made according to four points: a high index of clinical suspicion, radiologic evidence of infection, repeated biopsies that are negative for malignancy, and positive results of microbiologic tests. SBO typically manifests clinically in patients with diabetes and recurrent otitis externa; the infection usually extends inferiorly to the compact bone of the infratemporal fossa, affecting the lower cranial nerve foramina. Several image-based techniques should be used to diagnose SBO. CT is the best option for evaluating bone erosion and demineralization, MRI can help delineate the anatomic location and extent of disease, and nuclear imaging is useful for confirming bone infection with high sensitivity. However, the standard diagnostic procedure for SBO is for patients to undergo repeated biopsies to rule out malignancy, with histopathologic signs of infection and detection of microorganisms in the biopsied bone or soft tissue indicating SBO. The ability to diagnose SBO can be increased by identifying patients at risk, recognizing the most important causes and routes of infection, describing the main radiologic findings, and always considering the differential diagnosis. ©RSNA, 2021.