Background The identification of high-risk patients with Heterozygous Familial Hypercholesterolemia (HeFH) that may benefit from early treatment is challenging. Coronary Artery Calcification (CAC) score accounts for coronary atherosclerotic burden. It has proven its accuracy in cardiovascular risk (CVR) assessment in the general population but data in HeFH are lacking. Objective The aim of our study was to assess CAC prevalence and its relationship with lifelong cholesterol exposure, calculated by Total Cholesterol Burden (TCB) in patients with HeFH. Methods 112 HeFH patients (50% males, median age 45) regularly followed-up since diagnosis were prospectively recruited at Pitié-Salpêtrière Hospital, Paris, France. CAC score was assessed using non contrast multi-detector computed tomography. TCB was calculated as total cholesterol (TC) x age at diagnosis plus annually assessed TC. Results The prevalence of CAC was 58%. Patients without CAC showed lower TCB than patients with CAC (298±110 vs 417.9±89 mmol-years/l, p<0.001). Among patients <45 (n=56), 39% exhibited CAC and a higher TCB compared to patients without CAC (352±71 vs 255±88 mmol-years/l, p<0.001) due to higher TC levels at diagnosis (10.2±2 vs 8.7±2 mmol/l, p=0.01). Multivariate analysis indicated that TCB was independently associated toCAC. Conclusions Asymptomatic HeFH subjects exhibit early coronary atherosclerosis directly associated with TCB. Cholesterol burden and CAC score may be useful to identify higher risk HeFH patients who can benefitfrom earlier and more aggressive treatment.