AbstractIntracoronary papaverine is used as a means to induce a strong and short‐lasting hyperemia in several recently developed methods to measure coronary flow reserve. Changes in stenosis geometry from papaverine would influence the measured coronary flow reserve. Therefore, we investigated the influence of intracoronary papaverine on stenosis geometry with quantitative analysis of the coronary angiogram and assessed the influence of papaverine on pressure‐flow characteristics of the stenosis and coronary flow reserve. The cross‐sectional areas (mean ± SD) of the stenosis increased 18% ± 7% after papaverine. The normal proximal and distal parts of the coronary artery dilated 5% ± 2% after papaverine. This results in a decrease of the calculated pressure drop over the stenosis varying from 20% to 30%. Coronary flow reserve of a flowlimiting epicardial stenosis is overestimated by 16% when papaverine is used to induce hyperemia. These papaverine‐induced changes can nevertheless be circumvented by maximal vasodilation of the major epicardial coronary artery with 3 mg intracoronary isosorbidedinitrate prior to the investigation of the coronary flow reserve with