The functional effects of coronary occlusive disease (COD) in cardiac transplant patients on small-resistance coronary vessels are unclear. We investigated the changes in coronary flow reserve (CFR) in response to the non-specific smooth muscle vasodilator papaverine. A 3F Doppler probe was inserted into the left anterior descending (LAD) coronary artery in 61 patients following orthotopic heart transplantation. Studies were performed in 57 males and 4 females with a mean age of 46 years (range 20–61 years). The median time from operation was 4 years (range 3 months to 10 years). Coronary blood velocity was measured at rest (RFV) and maximum hyperaemia (PFV) produced by intracoronary papaverine. Coronary flow reserve (CFR) was defined as the ratio of PFV to RFV. Minor lesions in epicardial vessels were found in 23 transplant patients. The mean percentage diameter of the most severe lesion in the coronary tree was 23% SD 3% including 12 lesions in the LAD coronary artery itself (mean 24% SD 4%). Patients with COD had an impaired CFR (2.6 SEM 0.2) compared with normals (3.9 SEM 0.2, P = 0.0003), adjusting for year after operation. Mean resting flow velocity was similar in both groups (minor COD, 6.8 cm/s SEM 1.2; normals, 7.1 cm/s SEM 0.6), but mean peak flow velocity response to papverine was reduced (16.5 cm/s SEM 2.5 versus 27.3 cm/s SEM 2.6; P = 0.007). In the presence of minor epicardial disease, coronary flow reserve in resistance vessels was reduced due to impairment of peak flow. This demonstrates that non-endothelial-dependent coronary resistance vessel vasodilatation is abnormal and may be caused by a defect in vascular smooth muscle function.