Background: Tumor necrosis factor alpha (TNF-α) is a major proinflammatory cytokine playing paramount role in the pathophysiology of inflammatory bowel disease (IBD). The identification of predictive biomarkers to establish response to treatment is intuitive and still unresolved need. A biomarker of TNF-α sensitivity would avoid unnecessary exposure of the patient to the drug and to its side effects. Objective: To investigate the relationship between immunohistochemical expression of TNF-α in the biopsies of ileocolonic segments in patients with activity of both ulcerative colitis (UC) and Crohn's disease (CD) and the clinicopathologic parameters and the response to treatment. Patients and methods: The study was conducted on 41 naïve patients diagnosed as IBD (UC and CD) and 15 normal subjects as a control group. All patients and control underwent full history taking (age, gender and clinical data as weight loss, diarrhea, bleeding, and duration of the disease), complete physical examination, laboratory investigation (Complete blood count (CBC), ESR, C-reactive protein (CRP), fecal calprotectin (FC)), colonoscopy disease localization, upper endoscope with upper GIT symptoms. Biopsies from the terminal ileum and different colon segments were taken for histopathological evaluation and immunohistochemistry was done according to published protocols to all cases and control. Results: Percentage and H-score for TNF-α significantly correlated with clinical severity and need to give additional treatment besides conventional therapy as anti-TNF therapy. Increased TNF-α expression is significantly associated with better response to anti-TNF treatment. Conclusion: Increased expression of TNF-α in the tissues is associated with the need to give additional treatment besides conventional therapy as anti-TNF therapy and also increased TNF expression is associated with better response to anti-TNF treatment.