INTRODUCTION: Mucosal healing (MH) has established as a long-term therapeutic goal for inflammatory bowel disease (IBD). Regenerative Islet-derived Protein 1alpha (reg1alpha) was reported to be closely related to gastrointestinal mucosal injury; however, its potential in monitoring MH remains unexplored. METHODS: Serum reg1alpha levels were quantified in 156 consecutive IBD patients (January 2021-December 2023) and stratified by endoscopic findings into MH (n = 136) and non-mucosal healing (NMH) groups. Diagnostic performance of reg1alpha was evaluated and compared to C-reactive protein (CRP) using receiver operating characteristic analysis. RESULTS: A total of 136 patients (85 with CD and 51 with UC) were finally included. Serum reg1alpha levels were significantly correlated with endoscopic activity. Patients in NMH group demonstrating markedly higher reg1alpha levels than those in MH group (92.6 vs. 55.5 ng/ml, p < 0.001). In UC, reg1alpha outperformed CRP in sensitivity (82.4% vs. 55.9%, p = 0.012) and accuracy (80.4% vs. 70.6%, p = 0.001) for monitoring MH. This superiority persisted in UC subgroups with non-or mild clinical symptoms. Combined index (reg1alpha + CRP) and multivariate model (incorporating clinical indices, reg1alpha and CRP) also enhanced sensitivity and accuracy over CRP alone in UC (all p < 0.05). However, reg1alpha showed no significantly higher efficacy in monitoring NMH compared to CRP in CD. In CRP-normal patients, patients with NMH had higher reg1alpha levels than those with MH in UC (77.6 vs. 49.8 ng/ml, p = 0.018), but not in CD. CONCLUSION: Reg1alpha represents as a novel and sensitive biomarker of endoscopic disease activity in patients with UC, even in patients with non- or mild clinical symptoms or normal CRP levels.