No data exist about successful percutaneous coronary intervention (PCI) and clinical outcome in patients with multiple coronary chronic total occlusions (CTOs). The aim of this study was to determine the impact on cardiac mortality of PCI of multiple CTOs. The Florence CTO PCI registry includes patients treated with drug-eluting stent for at least 1 CTO. From this registry, we examined consecutive patients with ≥2 CTOs. Patients were stratified into successful PCI of all attempted CTOs and partially successful PCI (1 CTO PCI successful) or failed PCI (no CTO PCI success) groups. The primary end point of the study was cardiac mortality. Of 1,035 patients with CTO, 120 (11.6%) underwent PCI for ≥2 CTOs for a total of 249 CTOs. CTO PCI was successful in 195 CTOs (78.3%), and in 76 patients (63.3%), PCI was successful in all attempted lesions, whereas in 34 patients, CTO PCI was partially successful and in 10, completely unsuccessful. Cardiac mortality at 12 months was lower in the CTO PCI success group than CTO PCI failure or partial success group (1.3% vs 11.3%; p = 0.025). The 2-year survival rate was lower in patients with a complete coronary revascularization compared with those with incomplete revascularization (96 ± 3% vs 78 ± 7%; p = 0.002); completeness of revascularization was inversely related to the risk of death (hazard ratio 0.10; p = 0.029). In patients with multiple CTOs, a successful PCI of all CTOs was associated with increased survival and completeness of revascularization was a strong predictor of survival.