Aim We sought to investigate the prognostic impact of the SYNTAX (Synergy between PCI with TAXUS and Cardiac Surgery) score (SS) on 1-year clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) undergoing medical therapy only. Methods and results Among the 13 819 patients enrolled in the ACUITY trial and undergoing coronary angiogram, 4491 patients were treated with medical therapy as the initial strategy. Of those, baseline SS and complete angiographic analysis were available in 1275 patients. Patients were divided in four groups based on the presence or absence of coronary artery disease (CAD) and subsequently, among patients with CAD, by SS. Major adverse cardiac events (MACE) and its individual components (death, myocardial infarction, and unplanned revascularization) were compared between groups. Among the 1275 patients, the mean SS was 3.5 ± 7.0 (range 0–45). SYNTAX score was 0 in 842 patients, >0 and ≤5 in 170, >5 and ≤11 in 119, and >11 in 144 patients. The 1-year rates of MACE were higher in patients with CAD and higher SS. By multivariable analysis, the SS was a strong predictor of all adverse ischaemic events, including mortality. By receiver operator characteristic analysis, an SS cut-off of 8 showed the best prognostic accuracy for death and MACE. Conclusion In patients with NSTE ACS undergoing medical therapy, the SS, especially when >8, was shown to be a strong predictor of 1-year MACE, including mortality. This finding has important clinical implications for risk stratification of patients with NSTE ACS undergoing medical therapy after an initial angiogram.