PURPOSE: The insulin-like growth factor-1 receptor inhibitor teprotumumab is effective for thyroid eye disease (TED), but there is limited evidence on its long-term safety. We studied the long-term cardiovascular, renal, infectious, and safety outcomes of teprotumumab compared with intravenous (IV) glucocorticoids (GCs), oral GCs, and conservative treatment in patients with TED. DESIGN: Population-based cohort study. PARTICIPANTS: Patients with TED who initiated teprotumumab, GCs, or conservative treatment between January 1, 2020, and December 1, 2024, from 80 health care organizations in the United States. METHODS: Propensity scores were used to match baseline covariates including demographics, comorbidities, laboratory data, and medications. Cox proportional hazards models were used to calculate hazard ratios (HRs). MAIN OUTCOME MEASURES: Outcomes included all-cause mortality and the risks of new-onset cardiovascular diseases, renal diseases, infectious outcomes, and safety outcomes, including hearing loss, within 5 years after initiating treatments. RESULTS: Teprotumumab was associated with markedly lower all-cause mortality (teprotumumab vs IV GCs: HR 0.32, 95% CI 0.16-0.65; teprotumumab vs oral GCs: HR 0.20, 95% CI 0.10-0.39) and reduced risks of acute myocardial infarction (teprotumumab vs IV GCs: HR 0.37, 95% CI 0.15-0.95; teprotumumab vs oral GCs: HR 0.33, 95% CI 0.12-0.91), acute kidney failure (teprotumumab vs IV GCs: HR 0.54, 95% CI 0.31-0.94; teprotumumab vs oral GCs: HR 0.37, 95% CI 0.22-0.63), emergency department visits (teprotumumab vs IV GCs: HR 0.48, 95% CI 0.38-0.60; teprotumumab vs oral GCs: HR 0.60, 95% CI 0.48-0.75), hospitalizations (teprotumumab vs IV GCs: HR 0.31, 95% CI 0.23-0.40; teprotumumab vs oral GCs: HR 0.34, 95% CI 0.26-0.45), urinary tract infection (teprotumumab vs IV GCs: HR 0.60, 95% CI 0.41-0.89; teprotumumab vs oral GCs: HR 0.58, 95% CI 0.40-0.86), pneumonia (teprotumumab vs IV GCs: HR 0.37, 95% CI 0.22-0.61; teprotumumab vs oral GCs: HR 0.33, 95% CI 0.20-0.53), and severe sepsis (teprotumumab vs IV GCs: HR 0.24, 95% CI 0.10-0.64; teprotumumab vs oral GCs: HR 0.31, 95% CI 0.11-0.84). There was no difference in the risks of diabetes, chronic kidney disease, or inflammatory bowel disease, or complications requiring a hearing device, whereas there was a higher risk of hearing loss after starting teprotumumab compared with GCs (teprotumumab vs IV GCs: HR 2.43, 95% CI 1.67-3.55; teprotumumab vs oral GCs: HR 2.38, 95% CI 1.65-3.44). All-cause mortality was also markedly reduced in teprotumumab-treated patients when compared with patients receiving conservative treatment (HR 0.24, 95% CI 0.13-0.45). CONCLUSIONS: Treatment with teprotumumab compared with IV or oral GCs was associated with reduced risks of death and cardiovascular, renal, and infectious outcomes in patients with TED. Teprotumumab may result in fewer adverse outcomes than systemic GCs for treating TED. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.