Background: The SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery Score II (SS-II) can well predict 4-year mortality in patients with complex coronary artery disease (CAD), and guide decision-making between coronary artery bypass graft surgery and percutaneous coronary intervention (PCI). However, there is lack of data regarding the utility of the SS-II in patients with three-vessel CAD undergoing PCI treated with second-generation drug-eluting stents (DES). The purpose of the present study was to evaluate the ability of the SS-II to predict long-term mortality in patients with three-vessel CAD undergoing PCI with second-generation DES. Methods: Totally, 573 consecutive patients with de novo three-vessel CAD who underwent PCI with second-generation DES were retrospectively studied. According to the tertiles of the SS-II, the patients were divided into three groups: The lowest SS-II tertile (SS-II <= 20), intermediate SS-II tertile (SS-II of 21-31), and the highest SS-II tertile (SS-II >= 32). The survival curves of the different groups were estimated by the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard regression analyses were performed to evaluate the relationship between the SS-II and 5-year mortality. The performance of the SS-II with respect to predicting the rate of mortality was studied by calculating the area under the receiver operator characteristic (ROC) curve. The predictive ability of the SS-II for 5-year mortality was evaluated and compared with the SS alone. Results: The overall SS-II was 27.6 +/- 9.0. Among patients in the lowest, intermediate and the highest SS-II tertiles, the 5-year rates of mortality were 1.6%, 3.2%, and 8.6%, respectively (P = 0.003); the cardiac mortality rates were 0.5%, 1.9%, and 5.2%, respectively (P = 0.014). By multivariable analysis, adjusting for the potential confounders, the SS-II was an independent predictor of 5-year mortality (hazard ratio: 2.45, 95% confidence interval: 1.38-4.36; P = 0.002). The SS-II demonstrated a higher predictive accuracy for 5-year mortality compared with the SS alone (the area under the ROC curve was 0.705 and 0.598, respectively). Conclusion: The SS-II is an independent predictor of 5-year mortality in patients with three-vessel CAD undergoing PCI treated with second-generation DES, and demonstrates a superior predictive ability over the SS alone.