Background: Some patients admitted to surgery for pancreatic ductal adenocarcinoma (PDAC) or ampullary adenocarcinoma (AAC) are perioperatively diagnosed with advanced disease and thus unresectable pancreatic cancer (PC) (stage III or IV). These patients could instead benefit from neoadjuvant chemotherapy. The aims were to investigate 1) whether unresectable patients already preoperatively had higher plasma CA 19-9, IL-6 and YKL-40 than patients with resectable tumors; and 2) if high preoperative levels of these biomarkers predict short overall survival (OS) in patients going through surgery, thus indicating non-radical procedure. Methods: Preoperative blood samples were collected from 211 patients with PDAC (138 resectable, 73 unresectable (Stage III n = 15; Stage IV n = 58)) and 41 patients with AAC (28 resectable, 13 unresectable (Stage III n = 12; Stage IV n = 1)) included in the BIOPAC Study from December 2010 to December 2014. IL-6 and YKL-40 concentrations in plasma were determined by ELISAs (IL-6: R&D; YKL-40: Quidel). Results: Plasma IL-6 was significantly (p < 0.05) elevated in patients with unresectable tumors compared to patients with resectable tumors (9.5 vs. 7.4 ng/l), whereas CA 19.9 and YKL-40 were similar in the two groups (p > 0.40). IL-6 could predict resectability with AUC = 0.58 (95%CI: 0.50-0.65). Operated patients with high preoperative levels (above median) of the biomarkers had significantly (p < 0.02) shorter OS than operated patients with levels below median (CA 19-9: HR = 1.97, 95% CI 1.24-3.13; IL-6: HR = 1.79, 1.13-2.82; YKL-40: HR = 1.78, 1.11-2.84). Patients with two or three elevated biomarkers had significantly shorter OS than patients with no elevated biomarkers (p < 0.01) (HR = 3.34, 1.51-7.42; HR = 2.94, 1.26-6.91; for 2 and 3 elevated biomarkers, respectively). Conclusions: The combination of high preoperative plasma CA19-9, IL-6, and YKL-40 may be useful to identify a subgroup of patients with PDAC and AAC with poor prognosis. These patients operated for PC may benefit from either neoadjuvant chemotherapy or postoperative adjuvant chemotherapy with gemcitabine+nab-paclitaxel or FOLFIRINOX.