Background. One of the most important prognostic factors in periampullary and pancreatic cancers is perineural infiltration, whose preoperative detection could be decisive in selecting which patients should not undergo upfront surgery. We evaluated CA 19.9 and the Neutrophil-to-lymphocyte ratio (NLR) as preoperative predictors of perineural invasion (PNI). Methods: Retrospective analysis including patients with periampullary and pancreatic cancers who underwent curative resection from January 2013 to August 2023 in our institution. A univariate analysis and multivariate analysis were performed to analyze the association between the CA 19.9 and NLR with the existence of PNI. Results: A total of 136 patients were included in the study. PNI was observed in 95 (69.9%) patients. The selected cut-off points were NLR: 2.2 and CA 19.9: 37 U/mL. In univariate analysis, NLR (p=0.001) and CA 19.9 (p=0.006) were statistically significantly associated with PNI. In multivariate analysis, baseline NLR levels (p=0.012; OR: 1.95; 95%CI: 1.16-3.29) as well as CA 19.9 levels (p=0.026; OR: 1.67; 95%CI: 1.06-2.64) remained independent prognostic factors for PNI. The area under de ROC curves was 0.67 for CA 19.9 (p=0.004) and 0.72 for NLR (p<0.001). A sensitivity of 65.9% with a positive predictive value of 81.7% were obtained for CA 19.9, and a sensitivity of 62.1% with a positive predictive value of 84.3% were achieved for NLR. Conclusion: Preoperative CA 19.9 and NLR levels seem to be good predictors of PNI. In patients with normal levels of CA 19.9, preoperative NLR above of 2.2 should be an indication for neoadjuvant therapy.