Introduction: Evaluation of the collagen type I and III turnover, expression and quantity of collagenase IV (MMP2) and its specifi c tissue inhibitor (TIMMP2), extracellular RNA (exRNA), TNF-alpha and macrophage number in the tissue pattern of in-stent restenosis (ISR). Methods: The expression of collagen type I and III, MMP2 and TIMMP2, exRNA and proinfl ammatory markers has been evaluated in the tissue pattern of ISR taken from 19 dead patients using confocal and immunofluorescent microscopy. The synthesis and degradation rate of collagen type I was determined thereby of specific markers: PICP and CITP, respectively. Results: The ISR evolution is associated with extracellular matrix reorganization exhibited by collagen type I degradation rate increasing and denaturized collagen accumulation in neointimal zone. Th e quantitative value of PICP is reducing by up to 70-92% in moderate and severe degrees of ISR, while CITP marker elevates in a range of 4-5-fold. Consequently the CITP/PICP ratio has a 5 to 8 times rise in ISR.The excessive collagen type I splitting is associated with marked MMP2 activation, which is a result of TIMMP2 diminution, and MMP2/TIMMP2 ration was elevating correlatively to in-stent restenosis progression. Conclusions: 1. The extracellular matrix remodeling is a suitable phenomenon of the in-stent restenosis exhibited by more active degradation of collagen type I vs type III, and denatured collagen I accumulation in neointimal zone whilst MMP2 increased and TIMMP2 reduced. 2. The exRNA rise might be an important predictor of ISR, its pathogenetic value having as support the robust correlation with inflammation markers such as TNF-alpha și macrophages.