Non-invasive coronary CT angiography (CCTA) has the potential to characterize the composition of non-calcified coronary plaques. CT-density values characterized by Hounsfield Units (HU) may classify non-calcified plaques as fibrous or lipid-rich, but the luminal density caused by the applied contrast material influences HU in the plaques in vitro. The influence of luminal density on HU in non-calcified plaques in vivo is unknown. Hence the purpose of this study was to test whether plaque characterization by CCTA in vivo depends on luminal density. Two CCTA-scans using two different contrast protocols were obtained from 14 male patients with coronary artery disease. The two contrast protocols applied resulted in high and low luminal density. Eleven non- calcified and 13 calcified plaques were identified and confirmed by intravascular ultrasound. Luminal attenuation differed with the two contrast protocols; 326[284;367] vs. 118[103;134] HU (P < 0.00001). In non-calcified plaques mean HU-values was lower 48[28;69] vs. 11[−4;25] HU (P = 0.004) with the low density protocol. As a consequence three out of eleven non-calcified plaques (27%) were reclassified from fibrous (high) to lipid rich (low). For calcified plaques a less pronounced but still significant difference in HU-values was found with the low luminal density. 770[622;919] vs. 675[496;855] HU (P = 0.02). Conclusion: Non-calcified plaques can be identified and classified by CCTA. However, the luminal density affects the absolute HU of both non-calcified and calcified plaques. Characterization and classification of non-calcified plaques by absolute CT values therefore requires standardization of contrast protocols.