Abstract:AIM: To evaluate the efficacy and safety of a medium-dose intravenous methylprednisolone (IVMP) pulse regimen for moderate-to-severe active thyroid-associated orbitopathy (TAO), with change in clinical activity score (CAS) as the primary outcome. METHODS: This prospective interventional study was conducted at a tertiary eye care center in Bangladesh between February and November 2022. Patients with active moderate-to-severe TAO (CAS≥3) received IVMP totaling 4.0 g (500 mg daily for 3 consecutive days, followed by 500 mg every 3wk for 5 cycles). Clinical outcomes, including CAS, proptosis measured by Hertel exophthalmometry, best-corrected visual acuity (BCVA; logMAR), and intraocular pressure (IOP), were assessed at baseline and at 6mo. RESULTS: A total of 30 patients with active TAO were enrolled and completed the 6-month follow-up. The mean age of the participants was 38.63±12.11y, and 19 (63.3%) were male. The mean CAS decreased significantly from 3.66±1.03 to 0.87±0.63 (mean change −2.79±0.95; P<0.0001). The mean degree of proptosis decreased from 22.47±1.59 to 20.13±1.97 mm (−2.34±1.25 mm; P<0.0001). BCVA improved from 0.46±0.31 to 0.15±0.18 logMAR (−0.31±0.28; P=0.02). The mean IOP decreased from 16.80±3.56 to 14.93±1.73 mm Hg (−1.87±2.45 mm Hg; P<0.001). Eyelid swelling, conjunctival redness, chemosis, and retro-orbital pain resolved in more than 90% of patients. Adverse events, including transient increased IOP (26.66%), hyperglycemia (20.00%), and elevated SGPT (6.67%), were mild and reversible; no severe hepatic, cardiovascular, or psychiatric complications occurred. CONCLUSION: Medium-dose IVMP (4.0 g) significantly improve disease activity, proptosis, visual acuity, and IOP, with an acceptable safety profile. This regimen represents an effective and safer alternative to high-dose IVMP for active moderate-to-severe TAO, particularly in resource-limited settings. Larger, multicenter trials with longer follow-up periods are needed to confirm these findings.