Background: The Agatston coronary artery calcium (CAC) score provides robust cardiovascular disease risk prediction but upweights plaque area by a density factor. Density, however, has been shown to be inversely associated with events. Using CAC volume and density separately improves risk prediction, but it is unclear how to apply this method clinically. We aimed to evaluate the association between CAC density and cardiovascular disease across the spectrum of CAC volume to better understand how to incorporate these metrics into a single score. Methods: We performed an analysis of MESA (Multi-Ethnic Study of Atherosclerosis) participants with detectable CAC to evaluate the association between CAC density and events by level of CAC volume using multivariable Cox regression models. Results: In a cohort of 3316 participants, there was a significant interaction ( P <0.001) between CAC volume and density for coronary heart disease (CHD) risk (myocardial infarction, CHD death, resuscitated cardiac arrest). Models using CAC volume and density resulted in improvement in the C -index (0.703, SE 0.012 versus 0.687, SE 0.013) and a significant net reclassification improvement (0.208 [95% CI, 0.102–0.306]) compared with the Agatston score for CHD risk prediction. Density was significantly associated with lower CHD risk at volumes ≤130 mm ³ (hazard ratio, 0.57 per unit of density [95% CI, 0.43–0.75]), but the inverse association at volumes >130 mm ³ was not significant (hazard ratio, 0.82 per unit of density [95% CI, 0.55–1.22]). Conclusions: The lower risk for CHD associated with higher CAC density varied by level of volume, and volume ≤130 mm ³ is a potentially clinically useful cut point. Further study is needed to integrate these findings into a unified CAC scoring method.