During percutaneous coronary intervention, the reference segment is assessed angiographically. This report described the discrepancy between angiographic and intravascular ultrasound (IVUS) assessment of reference segment size in patients with type 2 diabetes mellitus. Preintervention IVUS was used to study 62 de novo lesions in 41 patients with type 2 diabetes mellitus. The lesion site was the image slice with the smallest lumen cross-sectional area (CSA). The proximal and distal reference segments were the most normal-looking segments within 5 mm proximal and distal to the lesion. Plaque burden was measured as plaque CSA/external elastic membrane (EEM) CSA. Using IVUS, the reference lumen diameter was 2.80 ± 0.42 mm and the reference EEM diameter was 4.17 ± 0.56 mm. The angiographic reference diameter was 2.63 ± 0.36 mm. Mean difference between the IVUS EEM diameter and angiographic reference diameter was 1.56 ± 0.55 mm. The mean difference between the IVUS reference lumen diameter and angiographic reference lumen diameter was 0.18 ± 0.44 mm. Plaque burden in the reference segment correlated inversely with the difference between IVUS and quantitative coronary angiographic reference lumen diameter (slope = −0.12, 95% confidence interval −0.17 to −0.07, p <0.001), but it was not related to the absolute angiographic reference lumen diameter. Thus, reference segment diameters in type 2 diabetic patients were larger using IVUS than angiography, especially in the setting of larger plaque burden. In conclusion, these findings combined with inadequate remodeling may explain the angiographic appearance of small arteries in diabetic patients.