Background: There is paucity of data concerning the optimal revascularization in patients with multivessel coronary artery disease (CAD) presenting non-ST-segment elevation acute coronary syndrome (NSTE-ACS). The aim was to evaluate long-term outcomes of patients with multivessel CAD presenting NSTE-ACS depending on the management after coronary angiography. Methods: 3,166 patients with NSTE-ACS hospitalized between 2006–2014 were screened. After exclusions, 1,342 patients were enrolled with multivessel CAD and were divided depending on their management after coronary angiography; the medical-only therapy group (n = 91), the PCI group (n = 1,122), the CABG group (n = 129). Propensity scores matching was used to adjust for differences in patient baseline characteristics. Results: After propensity score analysis, 273 well-matched patients were chosen. Both before and after matching, patients treated with a medical-only therapy were burdened with the highest percentage of 24-month all-cause death and non-fatal MI in comparison to PCI and CABG groups respectively. In the CABG group, ACS-driven revascularization rate was lowest. In the overall population, PCI (HR 0.33; 95% CI 0.20–0.53; p < 0.0001) and CABG (HR 0.54; 95% CI 0.31–0.93; p = 0.028) were independent factors associated with favorable 24-month prognosis. However, in a matched population only PCI was an independent predictor of long-term prognosis with a 63% decrease of 24-month mortality (HR 0.37; 95% CI 0.19–0.69; p = 0.0020). Conclusions: In patients with multivessel CAD presenting with NSTE-ACS, medical-only management is related with adverse long-term prognosis in contrast to revascularization, which reduces 24-month mortality, especially among patients undergoing percutaneous intervention. Performance of PCI is an independent factor for improving long-term prognosis. Background: There is paucity of data concerning the optimal revascularization in patients with multivessel coronary artery disease (CAD) presenting non-ST-segment elevation acute coronary syndrome (NSTE-ACS). The aim was to evaluate long-term outcomes of patients with multivessel CAD presenting NSTE-ACS depending on the management after coronary angiography. Methods: 3,166 patients with NSTE-ACS hospitalized between 2006–2014 were screened. After exclusions, 1,342 patients were enrolled with multivessel CAD and were divided depending on their management after coronary angiography; the medical-only therapy group (n = 91), the PCI group (n = 1,122), the CABG group (n = 129). Propensity scores matching was used to adjust for differences in patient baseline characteristics. Results: After propensity score analysis, 273 well-matched patients were chosen. Both before and after matching, patients treated with a medical-only therapy were burdened with the highest percentage of 24-month all-cause death and non-fatal MI in comparison to PCI and CABG groups respectively. In the CABG group, ACS-driven revascularization rate was lowest. In the overall population, PCI (HR 0.33; 95% CI 0.20–0.53; p < 0.0001) and CABG (HR 0.54; 95% CI 0.31–0.93; p = 0.028) were independent factors associated with favorable 24-month prognosis. However, in a matched population only PCI was an independent predictor of long-term prognosis with a 63% decrease of 24-month mortality (HR 0.37; 95% CI 0.19–0.69; p = 0.0020). Conclusions: In patients with multivessel CAD presenting with NSTE-ACS, medical-only management is related with adverse long-term prognosis in contrast to revascularization, which reduces 24-month mortality, especially among patients undergoing percutaneous intervention. Performance of PCI is an independent factor for improving long-term prognosis.