AbstractPost‐percutaneous coronary intervention (PCI) fractional flow reserve (FFR) ≥0.90 confers an improved cardiac prognosis. There are currently limited data available to determine how often it is possible to improve an angiographically acceptable but physiologically suboptimal result. A physiology‐guided optimization strategy can achieve a clinically meaningful increase in the proportion of patients achieving a final post‐PCI FFR ≥0.90 compared to standard care. Following angiographically successful PCI procedures, 260 patients will be randomized (1:1) to receive either a physiology‐guided incremental optimization strategy (intervention group) or blinded post‐PCI coronary physiology measurements (control group). Patients undergoing successful, standard‐of‐care PCI for either stable angina or non‐ST‐segment‐elevation myocardial infarction who meet the study's inclusion and exclusion criteria will be eligible for randomization. The primary endpoint is defined as the proportion of patients with a final post‐PCI FFR result ≥0.90. Secondary endpoints include change from baseline in Seattle Angina Questionnaire and EQ‐5D‐5L scores at 3 months and the rate of target vessel failure and its components (cardiac death, myocardial infarction, stent thrombosis, unplanned rehospitalization with target vessel revascularization) at 3 months and 1 year. 260 individual patients were successfully randomized between March 2018 and November 2019. Key baseline demographics of the study population are reported within. TARGET FFR is an investigator‐initiated, prospective, single‐center, randomized controlled trial of an FFR‐guided PCI optimization strategy. The study has completed recruitment and is now in clinical follow‐up. It is anticipated that primary results will be presented in Autumn 2020. ClinicalTrials.gov Identifier: NCT03259815. [Correction added on Apr 3 2020, after first online publication: Clinical Trials identifier added.]