BACKGROUND: Renal dysfunction, an important predictor of cardiovascular mortality, is paradoxically associated with a lower incidence of positive coronary fractional flow reserve (FFR) values, possibly due to renal disease-associated myocardial microvascular dysfunction. It is unknown if this relationship is influenced by arterial hypertension, a condition strongly associated with renal- and microvascular dysfunction. METHODS: The incidence of positive (<0.81) FFR values was retrospectively evaluated in consecutive patients with intermediate severity coronary artery lesions that were either associating or not associating renal dysfunction (creatinine clearance, CrCl <90 mL/min/1.73 m2), and had mild/moderate or severe arterial hypertension (treated by <3 or ≥3 different drugs). RESULTS: Positive FFR values were found in 49.5% of the 109 included patients, with a significantly lower incidence in those with renal dysfunction: 23 vs. 31 cases (39.7% vs. 60.8%, P=0.03). However, uni- and multivariate subpopulation analysis evidenced that renal dysfunction was a significant independent predictor of fewer positive FFR results only in severely hypertensive patients (univariate P values for mild/moderate and severe hypertension: 0.80 and <0.01, respectively; multivariate P in severely hypertensive patients: 0.04). This categorization significantly restricted the number of borderline FFR results (0.75-0.80) where measurement interpretation could be challenging because of renal dysfunction (from 13.8% to 4.6% of the whole study population, P=0.03). CONCLUSIONS: In the current study renal dysfunction was independently associated with a significantly higher incidence of negative FFR results in patients with intermediate severity coronary artery lesions only in the presence of severe arterial hypertension. This observation should be confirmed by large-scale prospective clinical trials.