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The objective of this study was to identify whether the preoperative platelet-lymphocyte (P/L) ratio might improve the predictive value of CA19-9 levels in stratifying a patient group with suspected periampullary malignancy who do not require staging laparoscopy.Patients with suspected periampullary cancer were identified from a prospectively maintained 10-year database. Only patients with resectable disease who underwent staging laparoscopy and subsequent laparotomy were included. Low-risk groups were stratified using a CA19-9 cutoff value of ≤ 150 kU/l (or ≤ 300 kU/l in patients with a concurrent bilirubin concentration > 35 μmol/l) and a P/L ratio value of ≤ 150.From 263 patients, preoperative CA19-9 levels and P/L ratios were available in 216 and 225 patients, respectively. The positive and negative predictive values for resectability, sensitivity, and specificity for CA19-9 levels ≤ 150kU/l were 83%, 36%, 51%, and 73%, respectively. For P/L ratios ≤ 150, these levels were 81%, 38%, 51%, and 72%, respectively. When combining the requirement for both CA19-9 levels and P/L ratios to be ≤ 150 (n = 38 out of 183), both positive predictive value (95%) and specificity (96%) were improved (Fisher exact test, P =.065 and P < .001, respectively); 21% of laparoscopies were avoidable when using these criteria. Increasing T stage (P = .005), vascular invasion (P < .001), perineural invasion (P = .008), and resection margin involvement (P < .001) were all associated with greater preoperative P/L ratios in resected periampullary adenocarcinoma (n = 204).The preoperative P/L ratio reflects an index of tumor invasiveness and merits prospective evaluation as an adjunct to CA19-9 in determining the requirement for laparoscopic staging in patients with potentially resectable periampullary malignancy.