Background. Pathologic studies have suggested that formation of neoadventitia is part of the subsequent development of restenosis/atheroma progression. Methods. We compared 45 pts who presented with drug-eluting stent (DES) failure to 30 pts with patent DES. IVUS measures were performed each 1 mm within the stent and stent edge. Vessel, stent, lumen, and intimal hyperplasia (IH) areas were measured. . The area of Neoadventitia (AD) was measured at the maximal IH site and maximum necrotic core(NC) site outside the external elastic membrane, and the composition of IH was assessed. Results. Pt age was 59짹8.95 yrs in DES failure vs 60짹9.14 yrs in patent DES; 33% of DES failures vs 25% of patent DES were diabetic. Mean follow up duration was 764짹946 days in DES failure. Stent length was shorter in patent DES than DES failure (p=0.001), however vessel size was similar. Minimal stent area was smaller in DES failure (4.70짹1.50 mm2 in DES failure vs 5.74짹1.63 mm2 in patent DES, p=0.012) and 30/45(66%) showed stent underexpansion (minimal stent area <5 mm2). DES failure showed larger AD area at the maximal IH area site (9.71짹2.74 mm2 in DES failure vs 6.67짹2.01 mm2 in patent DES, p=0.0002). More importantly, maximal NC area of IH was correlated with maximal AD area in DES failure (r=0.596, p=0.003). Conclusion. The periadventitia thickening may be associated with high biologic activity and subsequent atherosclerosis progression as an another mechanism of DES failure.