Background <p>Semaglutide, a glucagon-like peptide-1 receptor agonist, and resmetirom, a thyroid hormone receptor-β agonist, are approved therapies for noncirrhotic metabolic dysfunction–associated steatohepatitis (MASH) with moderate to advanced fibrosis. Their comparative economic value has not been established.</p> Objectives <p>To evaluate the cost-effectiveness of semaglutide and resmetirom compared with standard of care (SOC) in patients with noncirrhotic MASH and F2–F3 fibrosis.</p> Methods <p>A state-transition model simulated disease progression in a hypothetical cohort with F2–F3 fibrosis over 5- and 10-year horizons from a U.S. healthcare payer perspective. Clinical efficacy inputs were derived from phase 3 trials (ESSENCE and MAESTRO-NASH), with costs and utilities obtained from published sources. Scenario analyses incorporated semaglutide’s cardiovascular mortality benefit. Deterministic and probabilistic sensitivity analyses assessed uncertainty.</p> Results <p>Semaglutide was cost-effective versus SOC at 5 years (ICER, $42,200/QALY) and 10 years (ICER, $44,138/QALY). Resmetirom produced higher ICERs ($95,981/QALY at 5 years; $107,002/QALY at 10 years) but remained below a $150,000/QALY threshold. Inclusion of cardiovascular mortality benefits improved semaglutide’s ICER to $38,324/QALY. Probabilistic analyses showed semaglutide had the highest probability of cost-effectiveness across willingness-to-pay thresholds. Over a 10-year horizon, treatment of 100,000 patients with F2–F3 MASH was projected to prevent 270 cases of decompensated cirrhosis, 10 cases of hepatocellular carcinoma, and 1,040 liver-related deaths with semaglutide, compared with 310 cases of decompensated cirrhosis, 10 cases of hepatocellular carcinoma, and 1,180 liver-related deaths with Resmetirom.</p> Conclusions <p>Semaglutide demonstrated superior cost-effectiveness compared with SOC and resmetirom, with cardiovascular benefits further strengthening its economic value.</p> Clinical trial number <p>Not applicable.</p>