Background: Inflammation and ulceration of the intestinal mucosa occur repeatedly in patients with ulcerative colitis (UC), leading to numerous bouts of bleeding per rectum. Objective: To evaluate serum osteoprotegerin (OPG) level in cases who had ulcerative colitis and its correlation with disease activity. Patients and Methods: This case control was conducted at the National Liver Institute, Menoufia University on 89 patients. They were divided into two groups and were matched in age and gender: Group I: 50 patients with ulcerative colitis diagnosed utilizing colonoscopy and histopathological examination. Group II: 39 individuals who had normal colonoscopic findings (grossly and histopathologically) as a control group. Results: Differences in OPG readings between the control group and UC subgroups were statistically significant. The mean OPG level in patients with extraintestinal manifestations (EIM) was 596 ± 365 pg/ml, while the mean OPG level in patients without EIM was 384 ± 333 pg/ml. OPG levels were not significantly linked to the prevalence of extraintestinal symptoms. The concentration of OPG was positively correlated with disease severity. Conclusion: The present study suggested that serum osteoprotegerin can be considered as a novel biomarker for assessing ulcerative colitis activity.