The SYNergy between percutaneous intervention with TAXus drug-eluting stents and cardiac surgery (SYNTAX) score (SS) is an effective angiographic predictor of clinical outcomes in patients with multivessel coronary artery disease (MVD) undergoing percutaneous coronary intervention. It is not known whether this relation is independent of the number of diseased vessels. The aim of the present study was to assess the relation between the SS and major adverse cardiac events (MACE) in patients with single-vessel disease (SVD) and MVD undergoing percutaneous coronary intervention. In the ACUITY trial, the SS was determined in 2,627 patients undergoing percutaneous coronary intervention. The relation between the SS and the 1-year clinical outcomes was assessed according to SS tertiles: <5 (n = 441), ≥5 but <10 (n = 525), and ≥10 (n = 495) for SVD and <10 (n = 361), ≥10 but <18 (n = 401), and ≥18 (n = 404) for MVD. At 1 year of follow-up, the rate of MACE was 16.8%, 24.7%, and 23.7% for patients with MVD in the first, second and third tertiles, respectively (p = 0.02). The corresponding rates for those with SVD was 13.3%, 15.3%, and 19.1% (p = 0.01). In the patients with MVD, the SS independently predicted 1-year MACE (hazard ratio 1.02, 95% confidence interval 1.01 to 1.03; p = 0.002), myocardial infarction (hazard ratio 1.02, 95% confidence 1.00 to 1.04; p = 0.02), and cardiac death (hazard ratio 1.05, 95% confidence interval 1.02 to 1.09; p = 0.005). In patients with SVD, the SS independently predicted 1-year MACE (hazard ratio 1.03, 95% confidence interval 1.01 to 1.05; p = 0.0009) and myocardial infarction (hazard ratio 1.05, 95% confidence interval 1.02 to 1.07; p = 0.002). In the overall study cohort, the SS was an independent predictor of MACE and death, and MVD (vs SVD) was not. In conclusion, the SS is a useful angiographic predictive tool for patients with SVD and MVD.