The authors describe a 42-year-old woman with systemic xanthogranulomatosis and bilateral intraorbital tumors, who subsequently developed multiple lesions of the intracranial dura mater, spinal cord, retroperitoneum, pericardium, and mediastinum. Systemic xanthogranulomatosis is histologically similar to systemic Weber-Christian disease, except for the absence of subcutaneous panniculitis. Immunohistochemical studies suggest that this clinical entity can be differentiated from histiocytosis X, because foamy cells in systemic xanthogranulomatosis demonstrate macrophages but not T-zone histiocyte markers. Differentiation of this disease from other intracranial xanthogranulomas and treatment are discussed.