Glycemic variability (GV) confers a risk of cardiovascular events. In this study, we aimed to investigate whether long-term GV has an impact on coronary atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM). A total of 396 patients with T2DM who had coronary computed tomography angiography and laboratory data available at baseline and for follow-up evaluations median 2.3 (1.8-3.1) years were included. Fasting plasma glucose (FPG) was measured every 1-3 months, and HbA1c was measured quarterly. The coefficient of variation (CV) of HbA1c and FPG were calculated as measures of GV. Quantitative assessment of coronary plaques was performed by measuring the annual change and progression rate of total plaque volume (TPV). Significant progression was defined as annual TPV progression ≥ 15%. Multivariable regression analyses were used to assess the effects of GV on atherosclerosis progression. In the 396 patients, the annual change in TPV was 12.35 ± 14.23 mm , and annual progression rate was 13.36 ± 12.69%. There were 143 (36.11%) patients with significant progression, and they had a significantly higher CV-HbA1c (P < 0.001) and CV-FPG (P < 0.001) than those without significant progression. In multivariable regression analyses, both CV-HbA1c and CV-FPG were independent predictors of annual change in TPV CV-HbA1c: β = 0.241 (0.019-0.462), P = 0.034; CV-FPG β = 0.265 (0.060-0.465), P = 0.012, annual TPV progression CV-HbA1c: β = 0.214 (0.023-0.405), P = 0.029; CV-FPG β = 0.218 (0.037-0.399), P = 0.019, and significant atherosclerosis progression CV-HbA1c: odds ratio OR = 1.367 (1.149-1.650), P = 0.010; CV-FPG OR = 1.321 (1.127-1.634), P = 0.013. Long-term GV is associated with accelerated progression of coronary atherosclerosis independent of conventional risk factors in patients with T2DM. Trial registration ClinicalTrials.gov (NCT02587741), October 27, 2015; retrospectively registered.