OBJECTIVES: We sought to evaluate clinical outcomes of patients with diabetes mellitus in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, overall and by treatment arm. BACKGROUND: In the ACUITY trial, 13,819 patients with moderate- or high-risk acute coronary syndromes (ACS) were randomized to heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition (GPI), bivalirudin plus GPI, or bivalirudin monotherapy. Compared with heparin plus GPI, bivalirudin monotherapy resulted in similar protection from ischemic events with less major bleeding. Whether these results apply to patients with diabetes is unknown. METHODS: We evaluated the impact of diabetes on 30-day net adverse clinical outcomes (composite ischemia [death, myocardial infarction, or unplanned ischemic revascularization] or major bleeding), overall and by antithrombotic strategy. RESULTS: Diabetes was present in 3,852 randomized patients (27.9%). Compared with nondiabetic patients, diabetic patients had higher 30-day rates of net adverse clinical outcomes (12.9% vs. 10.6%; p < 0.001), composite ischemia (8.7% vs. 7.2%; p = 0.003), and major bleeding (5.7% vs. 4.2%; p < 0.001). Among diabetic patients, compared with heparin plus GPI, bivalirudin plus GPI resulted in similar rates of net adverse clinical outcomes (14.0% vs. 13.8%; p = 0.89), while bivalirudin monotherapy resulted in a similar rate of composite ischemia (7.9% vs. 8.9%; p = 0.39) and less major bleeding (3.7% vs. 7.1%; p < 0.001), yielding fewer net adverse clinical outcomes (10.9% vs. 13.8%; p = 0.02). CONCLUSIONS: Diabetic patients with ACS managed invasively have higher rates of composite ischemia and major bleeding. Compared with treatment with heparin plus GPI, bivalirudin monotherapy provides similar protection from ischemic events with less major bleeding, resulting in a significant reduction in net adverse clinical outcomes.