Background: Surgical site infections (SSIs) are extremely common in pancreatic surgery and explain its considerable morbidity and mortality, even in tertiary centers. Early detection of these complications, with the help of laboratory assays, improve clinical outcome. The aim of the present study is to evaluate C-reactive protein (CRP) diagnostic accuracy as early predictor of SSIs after pancreaticoduodenectomy (PD). Methodology: We considered 251 consecutive PD. We prospectively recorded preoperative clinical and anthropometric data, intraoperative details and the postoperative outcome. In the first pool of consecutive patients (n = 150), we analyzed CRP levels from postoperative day 1 to 7 and investigated the prediction of SSIs. We then validated the diagnostic accuracy on the following 101 consecutive cases. Results: At multivariate analysis, high BMI and preoperative biliary stenting appeared to be independently associated with SSIs and organ-space SSI development. The CRP cutoff of 17.27 mg/dl on postoperative day 3 (78% sensitivity, 79% specificity) and of 14.72 mg/dl on postoperative day 4 (87% sensitivity, 82% specificity) was in a position to predict the course of 78.2 and 80.2% of patients, respectively. Conclusions: CRP on postoperative days 3 and 4 seems able to predict postoperative course, selecting patients deserving intensification of diagnostic assessment; patients not satisfying these conditions could be reasonably directed toward early discharge.