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Lung cancer, chronic obstructive pulmonary disease, and cardiovascular disease are highly prevalent in the general population and expected to cause most deaths by 2050. For these “Big-3,” treatment might cure, delay, or stop the progression of disease at a very early stage. Lung nodule growth rate (a biomarker for lung cancer), emphysema/air trapping (a biomarker for chronic obstructive pulmonary disease), and coronary artery calcification (a biomarker for cardiovascular disease) are imaging biomarkers of early stages of the Big-3 that can be acquired with low-dose computed tomography (CT). We hypothesize that a (combined) low-dose CT examination for detection of all 3 diseases may significantly improve the cost-effectiveness of screening in the future. We review the current evidence of the imaging biomarkers for the detection of the Big-3 diseases and present the potential health economic potential of Big-3 screening. Furthermore, we review the low-dose CT protocols to acquire these biomarkers and describe the technical considerations when combining the CT protocols for the different biomarkers.