Background: Infectious complications are frequently encountered after abdominal surgery. Early recognition, diagnosis, and subsequent timely treatment is the single most important denominator of postoperative outcome. This study prospectively addressed the predictive value of routine assessment of C-reactive protein levels as an early marker for infectious complications after major abdominal surgery. Methods: Consecutive patients undergoing major abdominal surgery between November 2015 and November 2019 were prospectively enrolled. Routine C-reactive protein measurements were implemented on postoperative days 3, 4, and 5, and additional computed tomography examinations were performed on demand. The primary endpoint was the occurrence of Clavien-Dindo grade III or higher infectious complications. Results: Of 350 patients, 71 (20.3%) experienced a major infectious complication, and median time to diagnosis was 7 days. C-reactive protein levels were significantly higher in patients with major infectious complications compared to minor or no infectious complications. The optimal cut-off was calculated for each postoperative day, being 175 mg/L on day 3, 130 mg/L on day 4, and 144 mg/L on day 5, and corresponding sensitivities, specificities, and positive and negative predictive values were over 80%, 65%, 40%, and 92% respectively. Alternative safe discharge cut-offs were calculated at 105 mg/L, 71 mg/L and 63 mg/L on days 3, 4, and 5, respectively, each having a negative predictive value of over 97%. Conclusion: The C-reactive protein cut-offs provided in this study can be used as a discharge criterion or to select patients that might require an invasive intervention due to infectious complications. These diagnostic criteria can easily be implemented in daily surgical practice.