Background. Stent underexpansion is one of the cause of drug-eluting stent (DES) failure. Methods. We used virtual histology (VH) intravascular ultrasound (IVUS) to evaluate lesion characteristics in plaque contributing to stent underexpansion in 27 pts (30 lesions) that were amenable to VH analysis before and after DES implantation. Standard IVUS measures were performed every 1mm within lesion, stent, and stent edges. We divided the stented lesion and its references into 7 subsegments including proximal and distal edge, and evaluated the pre-intervention VH-IVUS (relative amounts of fibrous, fibrofatty, dense calcium, and necrotic core) and compared this analysis to post-DES stent dimensions. High-pressure stent deployment (>14 atm) was performed in all pts. Negative remodeling was defined as a remodeling index (lesion/reference vessel area) <0.95. Results. Pt age was 62짹12yrs, 60% were males, and 17% were diabetic. Using a standard definition (underexpansion=minimum stent area [MSA] <5mm2), 27/148 stent subsegments (18%) were underexpanded of which 11/27 underexpanded subsegments (41%) were located in the distal third of the stent. Underexpanded stents were found in lesions with a greater percentage of dense calcium and nectoric core within the stenosis (see Table) and a smaller distal reference vessel (vessel area of 8.6짹2.3 vs 14.5짹5.1mm2, p<0.0001 and lumen area of 4.0짹1.0 vs 6.9짹2.8mm2, p<0.0001). Remodeling index was lower in underexpanded stents (0.91짹0.17 vs 1.14짹0.49, p=0.0002). Conclusion: In vivo VH-IVUS analysis indicates that stent underexpansion occurs especially at the site of increased amounts of dense calcium and necrotic core. Negative remodeling is an important factor contributing to drug-eluting stent underexpansion