Background: Anastomotic leak (AL) after gastrointestinal surgery is a serious postoperative complication that leads to significant morbidity and mortality. Objective: To evaluate the role of sequential postoperative serum determinations of C-reactive protein (CRP) and Procalcitonin (PCT) in the identification and prediction of anastomotic leakage after gastrointestinal surgery and to describe the kinetics of PCT and CRP after surgery and their relative usefulness for the early detection of anastomotic leaks after gastrointestinal surgery. Patients and Methods: This study is a clinical prospective randomized observational analytical cross-sectional study conducted in the elective and emergency surgery theaters of the department of general surgery at Suez Canal university hospital from Jan 2015 to Jan 2016 on 45 patients who underwent small bowel, colonic and rectal surgery with resection and primary anastomosis. The data was collected using a questionnaire and lab results. Results: In our study, 22.2% of study patients developed anastomotic leakage, 48.9% of the studied population was between the ages of (46–60) (range 18-72 years), and 62.2% of the study populations were female. Both biochemical markers were elevated in patients with anastomotic leakage at day2, 3, and 4 and showed slightly similar curves, percentages but the upper hand was for PCT than CRP in the point of early detection and in the much more sensitive and more specific. The Pearson correlation with fistula was more powerful for CRP than for PCT. Conclusion: Patients with PCT greater than 0.65mg/dL and CRP greater than 21 mg/dL on Day4, even in the absence of clinical signs, are not permitted to leave the hospital and a diagnostic work-up for sepsis (lung, urinary tract, intra-abdominal, or wound) is actively pursued.