Background: Increased protease activity is a key pathological feature of inflammatory bowel disease (IBD). However, the differences in extracellular matrix remodelling (ECM) in Crohn’s disease (CD) and ulcerative colitis (UC) are not well described. An increased understanding of the inflammatory processes may provide optimized disease monitoring and diagnostics. We investigated the tissue remodelling in IBD and IBS patients by using novel blood-based biomarkers reflecting ECM remodelling. Methods: Five ECM biomarkers (VICM, BGM, EL-NE, C5M, Pro-C5) were measured by competitive ELISAs in serum from 72 CD patients, 60 UC patients, 22 patients with irritable bowel syndrome (IBS), and 24 healthy donors. One-way analysis of variance, Mann-Whitney U-test, logistic regression models, and receiver operator characteristics (ROC) curve analysis was carried out to evaluate the diagnostic accuracy of the biomarkers. Results: The ECM remodelling was significantly different in UC compared to CD. The best biomarker combination to differentiate UC from CD and colonic CD was BGM and VICM (AUC = 0.98, P<0.001; AUC = 0.97, P<0.001), and the best biomarker combination to differentiate IBD from IBS patients were BGM, EL-NE, and Pro-C5 (AUC = 0.8, P<0.001). When correcting for the use of immunosuppressant and elevated CRP levels (CRP>5mg/mL), correlation of Pro-C5 (r = 0.36) with CDAI was slightly improved compared to CRP (r = 0.27) corrected for the use of immunosuppressant. Furthermore, BGM and EL-NE biomarkers were highly associated with colon inflammation in CD patients. Conclusion: ECM fragments of tissue remodelling in IBD affect UC and CD differently, and may aid in differentiating IBD from IBS (EL-NE, BGM, Pro-C5), and UC from CD patients (BGM, VICM). Formation of type V collagen is related to the level of inflammation in CD and may reflect disease activity in CD.