Measurement of coronary flow reserve has been suggested as an adjunct to anatomic assessment of coronary stenoses in patients with ischemic heart disease. We compared papaverine hydrochloride and radiographic contrast to determine which agent was superior for the determination of coronary flow reserve. Coronary flow reserve was determined during cardiac catheterization by means of digital coronary angiography and parametric imaging. Two groups of patients were studied. Among patients in group 1, coronary flow reserve was determined by means of both papaverine and contrast. In group 1 patients with normal coronary arteries, papaverine-induced flow reserve was greater than contrast-induced reserve in all but one vascular region (n = 9, 4.98 ± 1.15 vs 3.56 ± 0.89; p = 0.29). Group 1 patients with coronary disease also demonstrated significantly greater flow reserve with papaverine (n = 25, 2.57 ± 0.20 vs 1.83 ± 0.11, p < 0.01). Group 2 included patients with single-vessel coronary artery stenoses. These patients were studied by means of either papaverine or contrast to determine coronary flow reserve for both the stenotic “ischemic” region and an adjacent nonstenotic, “nonischemic” region. Those patients in group 2 who wers studied by means of contrast had a modest difference between flow reserve values in the nonischemic and those in the ischemic regions (n = 15, 1.78 ± 0.10 vs 1.26 ± 0.09; p < .0001) with considerable overlap. Patients studied by means of papaverine had a much greater separation in flow reserve between nonischemic and ischemic regions (n = 22, 2.78 ± 0.19 vs 1.46 ± 0.14; p < 0.0001). We conclude that papaverine is superior to radiographic contrast for measuring coronary flow reserve in patients with ischemic heart disease, because of the greater degree of induced hyperemia and the ability to more accurately differentiate nonischemic from ischemic vascular regions in individual patients.