AIMS: Fractional flow reserve (FFR) is the reference standard for the assessment of the functional significance of coronary artery stenoses, but is underutilized in daily clinical practice. We aimed to study long-term outcomes of FFR-guided percutaneous coronary intervention (PCI) in the general clinical practice. METHODS AND RESULTS: In this retrospective study, consecutive patients (n = 7358), referred for PCI at the Mayo Clinic between October 2002 and December 2009, were divided in two groups: those undergoing PCI without (PCI-only, n = 6268) or with FFR measurements (FFR-guided, n = 1090). The latter group was further classified as the FFR-Perform group (n = 369) if followed by PCI, and the FFR-Defer group (n = 721) if PCI was deferred. Clinical events were compared during a median follow-up of 50.9 months. The Kaplan-Meier fraction of major adverse cardiac events at 7 years was 57.0% in the PCI-only vs. 50.0% in the FFR-guided group (P = 0.016). Patients with FFR-guided interventions had a non-significantly lower rate of death or myocardial infarction compared with those with angiography-guided interventions [hazard ratio (HR): 0.85, 95% CI: 0.71-1.01, P = 0.06]; the FFR-guided deferred-PCI strategy was independently associated with reduced rate of myocardial infarction (HR: 0.46, 95% CI: 0.26-0.82, P = 0.008). After excluding patients with FFR of 0.75-0.80 and deferring PCI, the use of FFR was significantly associated with reduced rate of death or myocardial infarction (HR: 0.80, 95% CI: 0.66-0.96, P = 0.02). CONCLUSION: In the contemporary practice, an FFR-guided treatment strategy is associated with a favourable long-term outcome. The current study supports the use of the FFR for decision-making in patients undergoing cardiac catheterization.