Background: Long‐term outcomes after percutaneous coronary intervention (PCI) relate in part to residual ischemia in the treated vessel, as reflected by post‐PCI fractional flow reserve (FFR). The strategy of FFR after PCI and treatment of residual ischemia—known as functionally optimized coronary intervention (FCI)—may be feasible and capable of improving outcomes. Methods and Results: Feasibility and results of FCI using an optical‐sensor pressure wire were prospectively evaluated in an all‐comer population with 50% to 99% lesions and ischemic FFR (≤0.80; ClinicalTrials.gov identifier NCT03227588). FCI was attempted in 250 vessels in 226 consecutive patients. The PCI success rate was 99.6% (249/250 vessels). FCI technical success—that is, FFR before and after PCI and PCI itself using the FFR wire—was 92% (230/250 vessels). Incidence of residual ischemia in the treated vessel was 36.5%. Approximately a third of these vessels (34.5%, n=29) were considered appropriate for further intervention, with FFR increasing from 0.71±0.07 to 0.81±0.06 ( P <0.001). Pressure wire pullback showed FFR ≤0.8 at distal stent edge was 7.9% and 0.7% proximal to the stent. FFR increase across the stent was larger in the ischemic than in the nonischemic group (0.06 [interquartile range: 0.04–0.08] versus 0.03 [interquartile range: 0.01–0.05]; P <0.0001) compatible with stent underexpansion as a contributor to residual ischemia. Conclusions: FCI is a feasible and safe clinical strategy that identifies residual ischemia in a large proportion of patients undergoing angiographically successful PCI. Further intervention can improve ischemia. The impact of this strategy on long‐term outcomes needs further study.