Several specific inflammatory diseases may affect the orbit either in isolation or as part of a systemic disease process. Many of these will present with tumefactive lesions that may mimic neoplasia. The classic features of inflammation, such as redness, swelling, pain and loss of function may be absent, which may also lead to the impression of neoplasia. The conditions covered in this chapter include the granulomatous diseases sarcoidosis and the xanthogranulomatous processes, Sjögren’s syndrome, the vasculitic diseases granulomatosis with polyangiitis (GPA or Wegener’s granulomatosis) and eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome), the recently recognized entity of IgG4-related disease, and the even more recently recognized VEXAS syndrome. Sjögren’s syndrome and IgG4-related disease also carry an increased risk of the development of lymphoma, as occurs in many other chronic inflammatory diseases. The disease processes in this chapter have specific clinicopathological features and their systemic manifestations may have significant impacts on the well-being of the patient, and establishing a diagnosis is of importance. A tissue biopsy is nearly always needed to establish a diagnosis, but additional serological tests may also be helpful.