Background Sex-specific differences affect the evaluation, treatment, and prognosis of coronary artery disease. We tested the hypothesis that long-term outcomes of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) are different between women and men. Methods and Results Consecutive 1090 patients, referred for PCI and undergoing FFR measurements at the Mayo Clinic between October 2002 and December 2009, were included in this registry study. Clinical events were compared between the sexes during a median follow-up of 50.9 months. Of all patients, women had higher FFR adjusted by visual coronary stenosis than men (P=0.03). The Kaplan-Meier percent of major adverse cardiac events at 5 years was 35% in women and 38% in men (P=0.54). Interestingly, in patients undergoing PCI with an FFR <0.75, the incidence of death or myocardial infarction was significantly higher in women than in men (hazard ratio, 2.16; 95% confidence interval, 1.04-4.51; P=0.04). Moreover, compared with patients with FFR >0.80, deferral of PCI for those with FFR between 0.75 and 0.80 was associated with an increased rate of major adverse cardiac events, particularly death or myocardial infarction in women (hazard ratio, 3.25; 95% confidence interval, 1.56-6.74; P=0.002) and revascularization in men (hazard ratio, 2.66; 95% confidence interval, 1.66-4.54; P<0.001). Conclusions Long-term outcome differs between women and men undergoing FFR-guided PCI. Our data suggest that the sex-based treatment strategy is necessary to further optimize prognosis of patients with coronary artery disease.