Skull base osteomyelitis (SBO) is a potentially life-threatening inflammation of cranial base bony structures of variable origin. Criteria for diagnosis and treatment are still controversial. Demographics, predisposing factors, symptoms, imaging, and clinical, laboratory, histological, and microbiological data of patients managed for SBO at the University Hospital of Brescia (ASST Spedali Civili) between 2002 and 2017 were retrospectively reviewed. Patients were included in different etiological groups. The topographic distribution of magnetic resonance (MR) abnormalities was recorded on a bi-dimensional model of skull base, on which three different patterns of inflammatory changes (edematous, solid, or necrotic) were reported. In patients with a history of radiotherapy, the spatial distribution of SBO was compared with irradiation fields. The association between variables and etiological groups was verified with appropriate statistical tests. A classification tree analysis was performed with the aim of inferring a clinical-radiological diagnostic algorithm for SBO. The study included 47 patients, divided into 5 etiological groups: otogenic (n = 5), radio-induced (n = 16), fungal (n = 14), immune-mediated (n = 6), and idiopathic (n = 6). At MR, five types of topographical distribution were identified (central symmetric, central asymmetric, orbital apex, sinonasal, maxillary). In patients with a history of radiotherapy, the probability to develop SBO was significantly increased in areas receiving the highest radiation dosage. The analysis of patients allowed for design of a classification tree for the diagnosis of SBO. The integration of clinical and radiologic information is an efficient strategy to categorize SBO and potentially guide its complex management.