Background: Ulcerative colitis (UC) has worldwide distribution and affects an increasing number of people. Calprotectin (CP) was found to be used to discriminate high fatigue scores among UC patients. Objective: The aim of the current study is the assessment of the relation between ulcerative colitis (UC) disease activity scores and fecal calprotectin (FCP) levels and patients' quality of life (QOL) and sensation of body fatigue. Patients and methods: A total of 51 newly clinically diagnosed UC patients underwent evaluation of disease activity using the Simple Clinical Colitis Activity Index (SCCAI) and Mayo's Disease Activity Index (DAI) and for QOL and fatigue using the Inflammatory Bowel Disease-QOL and IBD-Fatigue Questionnaires (IBD-QOL-Q, IBD-FQ). Serum C-reactive protein (CRP) and FCP levels were estimated. Results: About 53% of patients had 3-4 UC diagnostic criteria with median values for SCCAI score and Mayo's DAI of was 6 (IQR=3-8) and 6 (IQR=5-9), respectively. A total of 27 patients had scores on IBD-QOL-Q and IBD-FQ above the median value. A total of 28 patients had serum CRP ≥9 and 26 patients had FCP level ≥150. Regression analysis defined high score for the night bowel (NB) motion frequency (β=0.476, P<0.001), rectal bleeding (β=0.269, P<0.001), old age (β=0.165 P=0.014), IBD-FQ (β=0.180, P=0.022) and urgency (β=0.180, P=0.022) as predictors for high IBD-QOL-Q score and the Receiver Operating Characteristic (ROC) curve analysis defined high score for NB motion frequency as the significant predictor for a score of 98 on IBD-QOL-Q. Combined scoring of the frequency of number of bleeding motions, stool urgency, rectal bleeding and high FCP levels could be used to discriminate patients with high fatigue scores and FCP can discriminate patients with score >60 with PPV of 85.29% (95%CI: 73.79-84.11%) and accuracy rate of 74.51% (95%CI: 60.37-85.67%). Conclusion: IBD badly affects patients QOL and this effect is related to disease severity and severity of differential symptoms especially the NB frequency, urgency and severity of rectal bleeding.