Fractional flow reserve (FFR) allows for physiological definition of coronary lesion severity but requires induction of maximal coronary circulation hyperemia with administration of adenosine leading to coronary resistive vessel vasodilatation. However, the hyperemic response to adenosine, and therefore the calculation of FFR, may be affected by dysfunction of the coronary microvasculature. The aim was to define the relationship between basal Pd /Pa and FFR and identify lesion-independent predictors of the change in Pd /Pa with hyperemia. One hundred and sixty-six consecutive patients undergoing FFR measurement were prospectively enrolled (mean age 62.6 ± 10.3 years, 27% females). Basal Pd /Pa , FFR, and delta Pd /Pa (difference between basal Pd /Pa and FFR) were recorded. Independent predictors of delta Pd /Pa included angiographic lesion severity, lesion length, gender, body mass index, and total cholesterol:HDL cholesterol ratio. The best basal Pd /Pa cutoff value to predict lesion physiological significance was 0.87 (positive predictive value of 100% for an FFR value ≤0.80) and the best cutoff for nonsignificance was 0.93 (negative predictive value of 98% for an FFR value >0.80). The delta Pd /Pa may be affected by patient gender, body mass index, and cholesterol profile. A basal Pd /Pa value of ≥0.93 is highly predictive of an FFR >0.80. Conversely, a basal Pd /Pa value of ≤0.87 is highly predictive of an FFR ≤0.80. © 2017 Wiley Periodicals, Inc.