BACKGROUND: Randomized clinical trials have shown that semaglutide is associated with a clinically relevant reduction in body weight and a lower risk of adverse cardiovascular events in those who are overweight or obese with a history of cardiovascular disease but no diabetes. The objective of this study was to assess the cost-effectiveness of semaglutide for this indication. METHODS: A decision analytic Markov model was used to compare the lifetime benefits and costs of semaglutide 2.4-mg subcutaneous weekly vs standard care in a hypothetical cohort of patients who were overweight or obese with preexisting cardiovascular disease (and no diabetes) from the health care payer perspective. Our model included ischemic stroke, heart failure hospitalization and/or urgent visit or myocardial infarction, and death over monthly transition cycles. Model outcomes included costs (2023 CAD$), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. RESULTS: Base case analysis showed that the incremental cost-effectiveness ratio for semaglutide compared with standard care was $72,962 per QALY gained with a 14% likelihood of cost-effectiveness adopting a $50,000 per QALY gained willingness to pay threshold. Factors with the greatest influence on cost-effectiveness were medication efficacy on mortality and medication cost. When the price of semaglutide was reduced by 50%, it was economically attractive at $37,190 per QALY gained with an 80% likelihood of cost-effectiveness at a $50,000 per QALY threshold. CONCLUSIONS: Semaglutide might be a cost-effective option for the publicly funded health care system contingent on initial pricing. Considering the candidate population-patients who are overweight or obese with preexisting cardiovascular disease-policymakers should consider the budget effect of funding semaglutide and weigh it against other ways scarce health care dollars might be used.