Background: Trefoil factor-3 (TFF3) is primarily expressed by small intestine and colon goblet cells. Several studies have revealed that it plays a crucial function in mucosal protection and gastrointestinal tract repair. Objective: to evaluate the significance of TFF3 as a marker of disease activity in ulcerative colitis (UC) patients. Methods: A hospital-based case control study was done on 40 active-UC patients, 40 patients in remission state who underwent colonoscopy and 40 non-ulcerative colitis healthy individuals as control group. Serum TFF3 was measured by ELISA and compared to C-reactive protein (CRP) and fecal calprotectin (FC) values. Clinical and endoscopic assessment was scored according to Lichtiger Index and ulcerative colitis endoscopic severity index (UCEIS). Results: Serum TFF3 was significantly correlated with Lichtiger Index (r=0.671), UCEIS (r=0.642), FC (r=0.8048) and CRP (r=0.3759). Serum TFF3 cutoff point <4.25 ng/ml indicated remission with a specificity 69.2%, 69%; sensitivity 92%, 97% for endoscopic and clinical indices respectively. Also, TFF3 significantly differentiated between mild, moderate, and severe diseases. The AUC of TFF3+FC was significantly higher than that of TFF3 and FC alone for predicting UC remission. Conclusion: Serum TFF3 is significantly correlated with clinical, endoscopic indices and FC in UC patients. Serum TFF3 is a powerful predictive biomarker of remission alone and in combination with FC in UC patients.