Background: Early detection and treatment of a colorectal anastomotic leak reduces leak-associated morbidity. The primary objective of this study was to assess the role of C-reactive protein (CRP) as a tool to facilitate the early diagnosis of large bowel anastomotic leak. Patients and Methods: We conducted a prospective observational study at a specialized colorectal unit of a tertiary referral teaching center where we recorded CRP levels pre-operatively and on day three for 113 patients undergoing a large bowel anastomosis. The primary outcome measure was the occurrence of anastomotic leak and its association with post-operative day three CRP levels (day one considered as 24 hours after surgery). The area under the curve of the receiver operating characteristic (ROC) curve analysis for the day three CRP value with the anastomotic leak was calculated and optimal cutoffs derived. Definitions and diagnostic criteria for a leak were established before commencing the study. Demographic, operative, diagnostic, and interventional procedure data were also recorded. Results: Twenty-two patients had an anastomotic leak (19.4%), and 14 (12.3%) required re-exploration or drain placement. The cutoff value of day three CRP with the greatest area under the ROC curve in the ROC curve analysis was 166 mg/L (area under the curve [AUC], 0.853) for open and laparoscopic procedures (sensitivity and specificity of 81.81% and 82.42%, respectively) with a negative predictive value of 93.8%. There was no difference in mean day three CRP levels between open and laparoscopic surgery (116.57 mg/L vs. 108.94 mg/L) Conclusions: A CRP value of more than 166 mg/L on day three should raise suspicion of an anastomotic leak.