INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists represent efficacious therapies for treating type 2 diabetes. Oral semaglutide is the only orally administered GLP-1 receptor agonist currently available and has been associated with reductions in glycated hemoglobin and body weight versus once-daily injectable liraglutide after 52 weeks in the PIONEER 4 clinical trial. As lower-cost liraglutide formulations have recently been developed, the present analysis evaluated the long-term cost-effectiveness of oral semaglutide 14 mg versus liraglutide 1.8 mg at lower acquisition costs in the UK. METHODS: The published and validated PRIME Type 2 Diabetes Model was used to project clinical and cost outcomes over patient lifetimes. Baseline cohort characteristics, as well as treatment-specific changes in physiological parameters and hypoglycemia rates, were sourced from PIONEER 4. Patients were modeled to receive oral semaglutide or liraglutide until HbA1c exceeded 8.0% (64 mmol/mol), after which treatment was intensified to basal insulin. Annual disutilities associated with treatment administration were applied to capture the differential impact of a once-daily oral versus once-daily injectable medication on quality of life. Costs, expressed in 2022 pounds sterling (GBP), were calculated from a National Health Service (NHS) perspective. The acquisition cost of liraglutide was reduced by up to 50% at increments of 5% across a range of scenarios. RESULTS: Oral semaglutide was associated with improved quality-adjusted life expectancy of 0.18 quality-adjusted life years versus liraglutide 1.8 mg due to a reduced incidence of diabetes-related complications and a reduced treatment-administration burden. Direct, per-person complication costs were estimated to be GBP 187 lower with oral semaglutide. Oral semaglutide remained dominant or cost-effective in the majority of scenarios, even with liraglutide price reductions of 50% applied. CONCLUSIONS: Oral semaglutide 14 mg was projected to be cost-effective versus lower-cost liraglutide 1.8 mg in the UK.