During thermodilution-based assessment of volumetric coronary blood flow, we observed that intracoronary infusion of saline increased coronary flow. This study aims to quantify the extent and unravel the mechanisms of saline-induced hyperemia. Thirty-three patients were studied; in 24 patients, intracoronary Doppler flow velocity measurements were performed at rest, after intracoronary adenosine, and during increasing infusion rates of saline at room temperature through a dedicated catheter with 4 lateral side holes. In 9 patients, global longitudinal strain and flow propagation velocity were assessed by transthoracic echocardiography during a prolonged intracoronary saline infusion. Taking adenosine-induced maximal hyperemia as reference, intracoronary infusion of saline at rates of 5, 10, 15, and 20 mL/min induced 6%, 46%, 111%, and 112% of maximal hyperemia, respectively. There was a close agreement of maximal saline- and adenosine-induced coronary flow reserve (intraclass correlation coefficient, 0.922; P<0.001). The same infusion rates given through 1 end hole (n=6) or in the contralateral artery (n=6) did not induce a significant increase in flow velocity. Intracoronary saline given on top of an intravenous infusion of adenosine did not further increase flow. Intracoronary saline infusion did not affect blood pressure, systolic, or diastolic left ventricular function. Heart rate decreased by 15% during saline infusion (P=0.021). Intracoronary infusion of saline at room temperature through a dedicated catheter for coronary thermodilution induces steady-state maximal hyperemia at a flow rate ≥15 mL/min. These findings open new possibilities to measure maximal absolute coronary blood flow and minimal microcirculatory resistance.