Abstract Disclosure: S. Ugradar: Consulting Fee; Self; Acelyrin. S.T. Wester: Advisory Board Member; Self; Amgen Inc. Consulting Fee; Self; Immunovant, Lassen. Research Investigator; Self; Amgen Inc, Sling, Immunovant. R. Holt: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. Q. Fu: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. G.J. Kahaly: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc. Introduction: Tobacco exposure is a known risk factor for Thyroid Eye Disease (TED) development and severity. Here, we compare outcomes with teprotumumab in smokers versus non-smokers as reported in pooled clinical trials in patients with acute TED. Methods: Patients ≥18 years old from two placebo-controlled trials and an open-label extension in the US and EU (Phase 2, NCT01868997; OPTIC, NCT03298867; OPTIC-X, NCT03461211) and one placebo-controlled trial in Japan (OPTIC-J, jRCT2031210453) with Graves’ disease and recent onset (≤9 month duration) active TED (Clinical activity score, CAS≥4), were included. Patients received eight infusions of teprotumumab over 21 weeks, with the final study visit at Week 24 (three weeks after final dose). Statistical analyses were conducted to test differences in responder rates for proptosis (≥2mm, primary outcome), diplopia (Bahn-Gorman scale≥1), clinical activity score (CAS, 2-point improvement), and Overall response (proptosis + CAS), as well as proptosis mm change and Graves’ Ophthalmopathy Quality of Life (GO-QOL, range 0-100) score change. Cochran-Mantel-Haenszel tests were conducted to test the difference in responder rate for proptosis, diplopia, CAS, and Overall responder rate between smokers and non-smokers stratified by study (Phase 2, OPTIC, OPTIC-X, and OPTIC-J). Mixed Model for Repeated Measures was conducted to test the difference in the mean change in proptosis and GO-QOL. Results: Baseline characteristics and TED characteristics between teprotumumab-treated smokers (N=32, mean age 51 years, 75% female) and non-smokers (N=116), mean age 49.5 years, 68% female were similar. No significant differences were seen in proptosis (78.1% vs 83.6%, P=.585), diplopia (55.6% vs 70.2%, P=.175), CAS (73.3% vs 59.3%, P=.145), Overall (73.3% vs 76.1%, P=.814) responses and GO-QOL least squares mean (LSM) change (17.3 vs 17.0, P=.927) between smokers and non-smokers. The magnitude of LSM proptosis mm change was similar (-2.82 vs -3.23 mm, P=.19). Conclusion: In this post-hoc assessment, proptosis response rates with teprotumumab were comparable in smokers and non-smokers at Week 24. Teprotumumab produced clinically relevant decreases in proptosis, CAS, Overall response, diplopia, and improvements in quality of life over the study period of 24 weeks in both groups. These improvements were comparable to those seen in the overall teprotumumab-treated patient populations with TED. Smoking is a known risk factor for more severe TED but does not significantly affect response to teprotumumab. Public Presentation: 6/2/2024