Objectives:The aim of this study was to evaluate the role of the C-reactive protein (CRP) and white cell count (WC) in the prediction of anastomotic leakage (AL) in major abdominal surgery. Methods: Multicenter, prospective, and observational study of adult patients who underwent major abdominal surgery. CRP and hemogram were measured after post-operative day (POD) 3 and POD 5. Complications were classified according to the Clavien-Dindo classification. Diagnostic accuracy was evaluated by the area under the receiver operating characteristic curve (AUC). Results: A total of 97 patients were included in the study. The mean age was 63 ± 12 years and 47 (48%) were male. Colorectal (56%) and gastric cancer (36%) were the most frequent diagnoses. About 23% had post-operative complications, of which 5% had AL. The most significant predictive factor was the increase in CRP ≥ 2.84 mg/L among POD 3 and 5 (AUC, 0.99, sensitivity, 95.6%, specificity, 100%, positive likelihood ratio, 23.0). The accuracy of the other biomarkers was lower, CRP on POD 3 (AUC, 0.55), on POD 5 (AUC, 0.93), WC on POD 3 (AUC, 0.33), and POD 5 (AUC, 0.35). Conclusion: The increase of CRP among POD 3 and 5 was an early predictor of AL in adult patients with major abdominal surgery.