Intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) reduces the risk for clinical events in patients with acute coronary syndromes (ACS), compared with angiographic guidance. However, the benefits of IVUS guidance in high-risk patients with diabetes with ACS is uncertain. The aim of this prespecified stratified subgroup analysis from the IVUS-ACS randomized trial was to determine the effectiveness of IVUS-guided PCI vs angiography-guided PCI in patients with diabetes with ACS. From August 20, 2019, to October 27, 2022, 1,105 patients with diabetes with ACS were randomized, including 554 patients in the IVUS-guided group and 551 in the angiography-guided group. The primary endpoint was the rate of target vessel failure (TVF) at 1 year, defined as the composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization. At 1-year follow-up, TVF occurred in 20 patients in the IVUS guidance group and in 46 patients in the angiographic guidance group (Kaplan-Meier rates 3.6% vs 8.3%; HR: 0.46; 95%CI: 0.27-0.81; P=0.007), driven by a reduction in clinically driven target vessel revascularization (0.9% vs 3.8%; P=0.003). IVUS-guided PCI also reduced the risk for TVF without procedural myocardial infarction (2.0% vs 6.7%; HR: 0.29; 95%CI: 0.15-0.57; P< 0.001) and all-cause mortality (HR: 0.30; 95%CI: 0.10-0.93; P=0.037). There were no significant differences in the rates of stent thrombosis or major bleeding between the groups. In the large-scale IVUS-ACS trial, IVUS-guided PCI improved 1-year clinical outcomes in high-risk patients with diabetes with ACS. (1-Month vs 12-Month DAPT for ACS Patients Who Underwent PCI Stratified by IVUS: IVUS-ACS and ULTIMATE-DAPT Trials; NCT03971500).