The impact of total plaque burden on absolute and relative amounts of each virtual histologic (VH) intravascular ultrasound (IVUS) plaque component has yet to be studied. We analyzed gray-scale and VH-IVUS findings in the first 990 patients enrolled in the 3,000+ patient global VH-IVUS registry. Whole pullback plaque burden and absolute and relative cross-sectional areas of fibrous tissue, fibrofatty plaque, dense calcium, and necrotic core were analyzed using a linear regression statistical model. Overall, absolute cross-sectional areas of each of the 4 plaque components correlated with total plaque cross-sectional area; however, the correlation between fibrous tissue and total plaque cross-sectional area was stronger than the correlation between fibrofatty plaque, dense calcium, or necrotic core and total plaque cross-sectional area. This was also true overall for each of the subgroups analyzed (gender, age, and presence/absence of acute coronary syndromes). Slope of the regression line relating each plaque component to overall plaque mass showed that 50% of the plaque cross-sectional area increase was because of fibrous tissue with a more gradual increase in fibrofatty plaque, dense calcium, and necrotic core. However, when comparing relative amounts of each plaque component with total plaque cross-sectional area, there was no significant relation between the increase in fibrous tissue, fibrofatty plaque, dense calcium, and necrotic core and the increase in total plaque cross-sectional area. In conclusion, only the absolute area of each plaque component correlated to overall plaque area, not the relative amount of each plaque; therefore, VH-IVUS plaque component increases must be analyzed by controlling for increases in plaque mass.