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Even after recanalization of a chronic total coronary occlusion, functional recovery is incomplete and parts of the myocardium remain hypoperfused. In this randomized, placebo-controlled, and double-blinded study, we investigated relative changes in myocardial perfusion and glucose metabolism induced by intracoronary administration of blood-derived circulating progenitor cells(CPCs), compared withthenatural coursein acontrol group after recanalization of total coronary occlusion. Methods: After recanalization of total coronary occlusion, 26 patients were randomly assigned to the CPC treatment or placebo group. Regional myocardial perfusion and glucose metabolism were assessed by 99mTc-tetrofosmin SPECT and 18F-FDG PET at baseline (after recanalization of total coronary occlusion) and 3 mo after the administration of 69 6 14 · 106 CPCs or cell-free serum, respectively. Segments were classified as ‘‘normal,’’ ‘‘perfusion‐metabolism mismatch’’ (dysfunctional segments with a 99m Tc-tetrofosmin‐ 18 F-FDGmismatch),or‘‘scar.’’ Results: In contrast to the placebo group, CPC administration resulted in a significant decrease in the number of segments with a perfusion‐ metabolism mismatch, from 3.0 6 0.5 to 1.7 6 0.6 segments (P , 0.05vs.baseline).Ofthenormalsegmentsatbaseline,2.7%inthe CPC group and 30% in the placebo group revealed a perfusion‐ metabolism mismatch at follow-up after 3 mo (P , 0.05 vs. placebo). Conclusion: Intracoronary administration of CPCs significantly reduces the amount of myocardium with a perfusion‐ metabolism mismatch and prevents areas with normal perfusion and metabolism after recanalization of total coronary occlusion from becoming dysfunctional during the next 3 mo. These results show that PET and SPECT can be used to monitor the effect of progenitor cells on myocardial integrity. More important, they provide evidence supporting expansion of the use of progenitor cell treatment to chronic coronary artery disease.