Noninvasive measurement of coronary flow reserve (CFR) (hyperemic/flow velocity ratio at rest) by transthoracic Doppler echocardiography showed normalization of flow in the left anterior descending (LAD) coronary artery early after stenting. We hypothesized that noninvasive CFR may reveal in-stent restenosis at follow-up. Therefore, we studied 134 patients, 0 to 72 months after successful proximal-middle LAD stenting, and 38 controls. LAD flow velocity was measured by transthoracic Doppler echocardiography during 90 seconds venous adenosine infusion (140 microg/kg/min). CFR was measured in diastole. According to angiography, patients who received stents were divided into 3 groups: group I, <50% LAD in-stent restenosis (n = 83); group II, nonsignificant (50% to 69%) LAD in-stent restenosis (n = 17); and group III, significant (> or = 70%) LAD in-stent restenosis (n = 34). LAD CFR was similar in group I and controls (2.90 +/- 0.58 vs 3.05 +/- 0.81; p = NS), it was slightly lower in group II (2.42 +/- 0.33) compared with controls and group I (p <0.001 vs both), and clearly abnormal (<2) in group III (1.38 +/- 0.48) compared with controls, and groups I and II (p <0.001). A CFR <2 had 91% sensitivity, 95% specificity, and 96% positive and 97% negative predictive values to detect significant stenosis in patients with LAD stents. Our data show that noninvasive Doppler assessment of CFR allows identification of significant LAD in-stent restenosis, based on a cut-off value of <2.