Purpose: To report the authors' experience with azathioprine and prednisone combination for adult periocular and orbital xanthogranulomatous disease. Methods: We identified 13 adults with histology-proven periocular or orbital xanthogranuloma in two tertiary referral orbital centres from 1984 to 2008. Patient records were reviewed and data collected on orbital localization, immune dysfunction, applied treatment and outcome. Results: Five patients with periocular or orbital xanthogranulomatous disease were fully treated with prednisone and azathioprine combination, which resulted in stabilization in two and regression in three. Two other patients had to discontinue azathioprine because of side-effects. Of the non-fully treated prednisone/azathioprine patients, four out of eight progressed. Conclusion: In adult periocular and orbital xanthogranuloma, combined treatment with prednisone and azathioprine yields adequate immunosuppression, often for a prolonged period of time.