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Background: Postoperative day (POD) 1 drain amylase concentration (DAC) is considered the most accurate predictor for the development of a clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD). Recent studies have associated drain placement with negative postoperative outcomes. This study aims to evaluate multiple biochemical markers and their associations with CR-POPF development in order to identify a reliable, non-drain dependent alternative to DAC. Methods: This is a review of 53 consecutive PD patients between 2021 and 2022. Albumin, C-reactive protein (CRP), C-reactive protein-to-albumin ratio (CAR), DAC, white blood cell count, and procalcitonin values were compared by CR-POPF status. The discriminatory abilities of CAR, CRP, and DAC for CR-POPF were compared using receiver operating characteristic (ROC) curves. Results: Six of 51 included patients developed a CR-POPF. Receiver operating characteristic curve analysis produced an area under the curve of.977 for POD 1 DAC (cut-off 5131.0 IU/L, sensitivity 100%, specificity 95.5%),.858 for POD 1 CRP (cut-off 52.5 mg/L, sensitivity 100%, specificity 72.7%), and 1.000 for POD 3 CAR (cut-off 99.2, sensitivity and specificity 100%). POD 3 CAR produced a positive and negative predictive value of 100%. Conclusion: The CAR and CRP provide early and accurate identification of patients with post-PD CR-POPFs. These markers offer a method of safe CR-POPF detection, when the gold standard DAC is unavailable, ultimately allowing for early intervention and patient rescue. [ABSTRACT FROM AUTHOR]