BackgroundWe aimed to compare coronary artery calcium scoring (CACS) with computed tomography (CT) with 80 and 120 kVp in a large patient population and to establish whether there is a difference in risk classification between the two scores.MethodsPatients with suspected CAD undergoing MPS were included. All underwent standard CACS assessment with 120-kVp tube voltage and with 80 kVp. Two datasets (low-dose and standard) were generated and compared. Risk classes (0 to 25, 25 to 50, 50 to 75, 75 to 90, and > 90%) were recorded.Results1511 patients were included (793 males, age 69 ± 9.1 years). There was a very good correlation between scores calculated with 120 and 80 kVp (R= 0.94,R2= 0.88,P< .001), with Bland–Altman limits of agreement of − 563.5 to 871.9 and a bias of − 154.2. The proportion of patients assigned to the < 25% percentile class (P= .03) and with CACS = 0 differed between the two protocols (n = 264 vs 437,P< .001).ConclusionIn a large patient population, despite a good correlation between CACS calculated with standard and low-dose CT, there is a systematic underestimation of CACS with the low-dose protocol. This may have an impact especially on the prognostic value of the calcium score, and the established “power of zero” may no longer be warranted if CACS is assessed with low-dose CT.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12350-022-03120-3.