Abstract Introduction Fractional flow reserve (FFR) is an invasive, lesion-specific surrogate for myocardial ischemia. The use of FFR to guide lesion selection for revascularization is believed to improve outcomes compared to an angiographic approach because it allows categorization of lesions based on hemodynamic significance. Lesions that are not hemodynamically significant can be safely deferred while the revascularization of significant lesions has been reported to improve quality of life compared to medical therapy alone. Purpose To compare the outcomes of patients randomized to the invasive (INV) arm of the ISCHEMIA trial who underwent FFR during initial angiography with those whose treatment was guided by angiography alone. Methods The ISCHEMIA data set was obtained from the National Heart, Lung, and Blood Institute under a data use agreement. Subjects randomized to the INV arm who underwent FFR were compared to those who underwent angiography alone. Categorial variables were compared using the chi-squared or Fisher’s exact test. Continuous variables were compared using the student T-test or Wilcoxon rank sum test. Multivariable linear mixed effects regression was used to evaluate the association of FFR use on SAQ7 AF score as well as assess changes across five years of follow-up. Covariates included in the model were based on their univariate and clinical significance. All tests were two-sided and P<0.05 was considered statistically significant. Results Of the 5,179 patients with chronic coronary syndromes and at least moderate ischemia on stress testing, 2588 were assigned to the INV strategy and 2210 had data available for analysis. Of these individuals, 410 (19%) had FFR performed during their diagnostic angiogram. Females comprised 24% of FFR patients and 24% of non-FFR patients (P=0.85). FFR patients were older than non-FFR patients (65.7 [8.7] years vs. 64.3 [9.6] years, P=0.006). The incidence of hypertension, diabetes, smoking, or prior MI at baseline did not differ between groups. Mean ejection fraction did not differ between groups. Fewer FFR patients had severe ischemia at baseline (45% vs. 52%) and more had mild or moderate ischemia (54% vs. 48%) (P=0.009). FFR patients had fewer native vessels with >70% stenosis than non-FFR patients (1.0[0.9] vs. 1.5[1.0], P<0.001), and less complex disease as assessed by the Duke jeopardy score (P<0.001). On multivariable linear mixed effects regression, FFR was not associated with a significant change in the SAQ AF score (0.56 (-0.85 – 1.97; P=0.44)), after adjusting for other covariates. However, the SAQ7 AF score was 0.22 units less in those that underwent FFR compared to those that did not (95%CI=-0.44 – -0.01; P=0.043) when assessed over follow-up time. Conclusion ISCHEMIA patients randomized to an INV strategy who underwent physiologic assessment with FFR had no improvement in angina frequency compared to those who underwent angiography alone.