Purpose: To compare the efficacy and safety of 6-weekly and 12-weekly intravenous methylprednisolone (IVMP) regimens in moderate-to-severe, active thyroid-associated orbitopathy (TAO) patients. Basic Procedures: Retrospective comparative study of patients who received IVMP between January 2011 and July 2021 at the Thyroid Eye Clinic, the Chinese University of Hong Kong. Outcome measures included the 7-item clinical activity score (CAS), exophthalmos, extraocular muscle motility (EOMy), marginal reflex distance (MRD), best corrected visual acuity (BCVA), intraocular pressure (IOP), the requirement of additional treatment, and complications. Main findings: A total of 65 (63% (41/65) females) moderate-to-severe, active TAO patients aged 50 ± 13 (25–74) years received 6-weekly (n = 22) or 12-weekly (n = 43) IVMP. Sex, age, smoking status, and Graves’ disease status were comparable in the two groups (allp> 0.05). CAS at week 6 (p= 0.0279), 12 (p= 0.00228), and 52 (p= 0.0228) were lower at each time for the 12-weekly group. Exophthalmos improved more at week 6 (p= 0.0453) and 12 (p= 0.0347) in the 12-weekly group. The improvement of diplopia, MRD1, MRD2, and EOMy were comparable between the two groups. More patients in the 6-weekly group (p= 0.00169) required additional treatments including IVMP+/−ORT. Patients in the 6-weekly group who did not require additional treatment had a lower presenting CAS (p= 0.0193) than those who required additional treatment. The total numbers of adverse events were comparable between the two groups.