We investigated predictors of major adverse cardiac events (MACE) with two years after medical treatment for lesions with angiographically intermediate lesions with intravascular ultrasound (IVUS) minimum lumen area (MLA) <4 mm² in non-proximal epicardial coronary artery. We retrospectively enrolled 104 patients (57 males, 62±10 years) with angiographically intermediate lesions (diameter stenosis 30–70%) with IVUS MLA <4 mm² in the non-proximal epicardial coronary artery with a reference lumen diameter between 2.25 and 3.0 mm. We evaluated the incidences of major adverse cardiovascular events (MACE including death, myocardial infarction, target lesion and target vessel revascularizations, and cerebrovascular accident) two years after medical therapy. During the two-year follow-up, 15 MACEs (14.4%) (including 1 death, 2 myocardial infarctions, 10 target vessel revascularizations, and 2 cerebrovascular accidents) occurred. Diabetes mellitus was more prevalent (46.7% vs. 18.0%, p=0.013) and statins were used less frequently in patients with MACE compared with those without MACE (40.0% vs. 71.9%, p=0.015). Independent predictors of MACEs with two years included diabetes mellitus (odds ratio [OR]=3.41; 95% CI=1.43–8.39, p=0.020) and non-statin therapy (OR=3.11; 95% CI=1.14–6.50, p=0.027). Long-term event rates are relatively low with only medical therapy without any intervention, so the cut-off of IVUS MLA 4 mm² might be too large to be applied for defining significant stenosis. The predictors of long-term MACE were diabetes mellitus and statin therapy in patients with angiographically intermediate lesions in non-proximal epicardial coronary artery.