Importance Nirmatrelvir-ritonavir is an oral antiviral recommended for treating high-risk individuals with COVID-19 in the community. However, there remains uncertainty over its cost-effectiveness in largely vaccinated populations and subgroups defined by age and clinical risk. Objective To compare the cost-effectiveness of nirmatrelvir-ritonavir vs usual care based on the UK Platform Adaptative Trial of Novel Antivirals for Early Treatment of COVID-19 in the Community (PANORAMIC) trial. Design, Setting, and Participants This economic evaluation was a within-trial cost-utility analysis conducted using data from the PANORAMIC trial and linked routine health care data from December 8, 2021, to September 30, 2024, adopting a UK National Health Service (NHS) and personal social services perspective over 6 months. Eligible participants were community-dwelling adults aged 50 years and older or ages 18 to 49 years with comorbidities. Data were analyzed from April 20, 2022, to September 30, 2024, for the nirmatrelvir-ritonavir group and December 8, 2021, to September 30, 2026, for usual care. Intervention Oral nirmatrelvir-ritonavir. Main Outcome and Measures Cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) of nirmatrelvir-ritonavir vs usual care. Results There were 1736 participants randomized to receive nirmatrelvir-ritonavir plus usual care (mean [SE] age, 54.7 [0.29] years), and 1768 to usual care alone (mean [SE] age, 54.8 [0.28] years); 2405 in the total cohort were female (69.2%]), and 3455 (98.6%) were vaccinated. Nirmatrelvir-ritonavir was cost-effective, on average, with lower total costs (£124; 95% CI, –£1207 to £1455) and higher QALYs (0.0110; 95% CI, 0.0062-0.0170) over 6 months compared with usual care (ICER, £10 897 per QALY). Nirmatrelvir-ritonavir had a 0.65 probability of being cost-effective at a £20 000 per QALY cost-effectiveness threshold, indicating decision uncertainty. The intervention remained cost-effective in most sensitivity analyses and prespecified subgroups, although several subgroup analyses were based on small sample sizes and should be interpreted as exploratory. Conclusions and Relevance In this economic evaluation of nirmatrelvir-ritonavir for COVID-19, cost-effectiveness varied by age, comorbidity, and vaccination status. Subgroup findings should be interpreted with caution, but targeted prescribing for at-risk adults aged 18 to 64 years, those aged 65 to 69 years, and adults aged 75 years and above, particularly those with comorbidities and not recently vaccinated, was likely to provide the greatest health system value; cost-effectiveness was not observed in low-risk adults aged 50 to 64 years, those aged 70 to 74 years, or in unvaccinated or recently vaccinated individuals.