Abstract Background The randomized, controlled FLAVOUR trial demonstrated that the clinical outcomes of the fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) strategy were non-inferior to the intracoronary ultrasound (IVUS)-guided PCI strategy. Purpose This study aimed to compare the difference in economic implications and health-related quality of life between the two strategies. Methods A total of 890 patients with intermediate stenosis in 9 sites in China from the FLAVOUR trial were included. Direct medical costs were calculated using a combination of resource-based and event-based methods. Health utility was defined as quality-adjusted life years and assessed based on the 19-item Seattle Angina Questionnaire. The primary analysis was a cost-utility analysis. Probabilistic sensitivity, one-way sensitivity, and subgroup analyses were performed. Results At two years, the average total cost per patient was Chinese yuan (CNY) 36,287±19,531 in the IVUS-guided group and CNY 29,237±19,239 in the FFR-guided group (ΔIVUS-FFR=CNY 7,050, p<0.001). The difference was driven primarily by the cost of initial admission (ΔIVUS-FFR=CNY 6,284, p<0.001). Quality-adjusted life years gained showed no significant differences between the two groups (FFR vs. IVUS: 1.639±0.086 years vs. 1.638±0.128 years, p=0.872). The probabilistic sensitivity and one-way sensitivity analyses revealed robust results. The subgroup analysis found that the cost reductions attributed to FFR guidance decreased in several subgroups, including patients with diabetes and those with high anatomical complexity. Conclusions In patients with intermediate stenosis, FFR-guided PCI is associated with significant cost savings compared with IVUS-guided PCI at two years and shows no differences in health-related quality of life outcomes.Central Illustration