(1) Serum leucine-rich α2 glycoprotein (LRG) has been reported as a useful biomarker for monitoring disease activity in patients with inflammatory bowel disease (IBD). We investigated whether serum LRG can differentiate patients with normal colonic mucosa from those with IBD or other forms of colitis. (2) Patients with diarrhea, abdominal pain, or bloody stools were consecutively enrolled at their initial visit to our hospital. Serum LRG and C-reactive protein were measured, and a colonoscopy and histology were performed. (3) We enrolled 317 patients (181 men, 136 women; median age: 51 years). Based on the endoscopic and histological criteria, 260 patients were diagnosed with ulcerative colitis (n = 134), Crohn's disease (n = 10), infectious colitis (n = 43), diverticular colitis (n = 17), or nonspecific colitis (n = 56). The remaining 57 patients were diagnosed with normal colonic mucosa including histology. The latter group's median LRG value (9.5 µg/mL, range: 5.8-13.5) was significantly lower than that of the other 260 patients (13.6 µg/mL, range: 6.8-62.7, < 0.0001). The optimal LRG cut-off value of <10.4 µg/mL was derived from the receiver operating characteristic (ROC) curve, showing a 91% sensitivity and 77% specificity for identifying patients with normal colonic mucosa. (4) serum LRG values < 10.4 µg/mL could be a useful biomarker for predicting patients with normal colonic mucosa.