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Abstract: Background: Little is known about the natural course of atherosclerotic plaque in the carotid artery bifurcation. This study investigated the growth pattern of calcifications in atherosclerotic carotid arteries and its determinants using serial multi-detector CT angiography (MDCTA). Methods: From a cohort of consecutive patients with TIA or ischemic stroke and a baseline MCDTA scan of the carotid arteries, subjects were invited for a follow-up scan after 4–6 years. Calcification volumes were scored semi-automatically on baseline and follow-up scans. Progression of calcification and its determinants were analyzed in two ways: 1. as incidence of newly detectable calcification in patients free of calcification at baseline, using logistic regression analysis; 2. as annual change in calcification volume in all patients, using linear regression analysis. Results: Two-hundred-twenty-two patients (aged 61.0 ± 9.6 years, follow-up time 4.7 ± 0.8 years) were included. Calcification volumes increased significantly (median 2.9 mm³ at baseline versus 9.4 mm³ at follow-up, p < 0.001). Newly detectable calcification during follow-up was found in 27 out of 67 patients without baseline calcification (40.3%) and was independently associated with age (OR 4.6 per 10 years increase in age, p < 0.001) and hypertension (OR 8.2, p = 0.008). Annual calcification growth was independently associated with age, calcification load, glucose, hypertension, and smoking. Baseline calcification load was the most important risk factor for calcification growth in multivariable analysis. Conclusion: Several modifiable cardiovascular risk factors are associated with carotid calcification growth, however, time and baseline calcification load remain the most important determinants of calcification development. [Copyright &y& Elsevier]