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Publisher Copyright: © 2022 The Authors Background: Despite a potential role of hemoglobin in atherosclerosis, data on coronary plaque volume changes (PVC) related to serum hemoglobin levels are limited. Objectives: The authors sought to evaluate coronary atherosclerotic plaque burden changes related to serum hemoglobin levels using serial coronary computed tomographic angiography (CCTA). Methods: A total of 830 subjects (age 61 ± 10 years, 51.9% male) who underwent serial CCTA were analyzed. The median interscan period was 3.2 (IQR: 2.5-4.4) years. Quantitative assessment of coronary plaques was performed at both scans. All participants were stratified into 4 groups based on the quartile of baseline hemoglobin levels. Annualized total PVC (mm3/year) was defined as total PVC divided by the interscan period. Results: Baseline total plaque volume (mm3) was not different among all groups (group I [lowest]: 34.1 [IQR: 0.0-127.4] vs group II: 28.8 [IQR: 0.0-123.0] vs group III: 49.9 [IQR: 5.6-135.0] vs group IV [highest]: 34.3 [IQR: 0.0-130.7]; P = 0.235). During follow-up, serum hemoglobin level changes (Δ hemoglobin; per 1 g/dL) was related to annualized total PVC (β = −0.114) in overall participants (P < 0.05). After adjusting for age, sex, traditional risk factors, baseline hemoglobin and creatinine levels, baseline total plaque volume, and the use of aspirin, beta-blocker, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and statin, Δ hemoglobin significantly affected annualized total PVC in only the composite of groups I and II (β = −2.401; P = 0.004). Conclusions: Serial CCTA findings suggest that Δ hemoglobin has an independent effect on coronary atherosclerosis. This effect might be influenced by baseline hemoglobin levels. (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411) publishersversion published