Background Total atherosclerosis disease burden is associated with clinical outcomes in patients with coronary artery disease. However, the influence of sex on the relationship between total anatomical and physiologic disease burdens and their prognostic implications have not been well defined. Methods and Results A total of 1136 patients who underwent fractional flow reserve (FFR) measurement in all 3 major coronary arteries were included in this study. Anatomical and physiologic total disease burden was assessed by SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score, residual SYNTAX score, a total sum of FFR in 3 vessels (3-vessel FFR), and functional SYNTAX score. The primary end point was major adverse cardiac events, a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization at 2 years. There were no differences in angiographic diameter stenosis, SYNTAX score, or residual SYNTAX score between women and men. However, both per-vessel FFR (0.89±0.10 versus 0.87±0.11, P<0.001) and 3-vessel FFR (2.72±0.13 versus 2.69±0.15, P<0.001) were higher in women. Multivariable Cox regression analyses showed that total anatomical and physiologic disease burdens were significantly associated with 2-year major adverse cardiac events, and there was no significant interaction between sex and total disease burden for clinical outcomes. Conclusions Despite similar angiographic disease severity, both per-vessel and per-patient physiologic disease severity was less in women than in men. There was no influence of sex on prognostic implications of total anatomical and physiologic disease burdens in patients with coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01621438.