Objective ·To investigate the effect of intraorbital injection of compound betamethasone on IgG4-related ophthalmic disease (IgG4-ROD). Methods ·Patients with IgG4-ROD who received intraorbital injection of compound betamethasone in the Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from September 2016 to August 2021 were included. The enrolled patients met the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease (IgG4-RD) and all had lacrimal gland involvement. The intraorbital administration regimen was 0.5 mL compound betamethasone (containing betamethasone propionate 5 mg/mL, and betamethasone sodium phosphate 2 mg/mL) into the affected orbit once a week for 6 weeks, and then once a month for 3 months. The drug was injected into the lacrimal gland and its surrounding superficial orbital tissue. For patients with extraocular muscle and optic nerve involvement, periocular injection was added. Before and after treatment, the IgG4-RD responder index (IgG4-RD RI) was recorded according to the clinical manifestations, serum IgG4 level and imaging findings. If recurrence was determined according to the IgG4-RD RI, maintenance treatment was adopted. Maintenance treatment regimen was once a month for 6 months, and then changed to bimonthly according to the doctor's judgment. Results ·According to the IgG4-RD RI before and after treatment, all patients achieved complete remission after initial treatment with remission periods of 4, 4, 6, and 5 months in case 1, 2, 3 and 4, respectively, but relapse occurred. Despite recurrence, case 1, 3, and 4 remained in remission with maintenance therapy in the follow-up of 50, 45, and 27 months, respectively. Due to the low total dosage of glucocorticoid, no obvious systemic and local side effects occurred during treatment. Also no serious injection-related side effects occurred. Case 2 refused maintenance therapy and the lacrimal gland returned to its original size after discontinuation, but did not aggravate further in the 47 months follow-up. Conclusion ·Intraorbital injection of compound betamethasone may be a useful treatment option for IgG4-ROD. However, patients require repeat injections due to relapse.