Aim The aim of this retrospective multicentre study was to evaluate the clinical and prognostic effect of fluorine-18-fluorodeoxyglucose (F-18-FDG)-PET/computed tomography (CT) in the restaging process of pancreatic cancer (PC). Materials and methods Data from patients treated for primary PC, who underwent F-18-FDG-PET/CT for suspicious of disease progression, were collected. Accuracy was assessed employing conventional diagnostic procedures, multidisciplinary team case notes, further F-18-FDG-PET/CT scans and/or follow-up. Receiver operating characteristic curve and likelihood ratio (LR+/-) analyses were used for completion of accuracy definition. Progression-free survival (PFS) and overall survival were assessed by using Kaplan-Meier method. The Cox proportional hazards model was used to identify predictors of outcome. Results Fifty-two patients (33 males and 19 females, with mean age of 59 years and range: 42-78 years) with PC were finally included in our study. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of F-18-FDG-PET were 85, 84, 90, 76, and 84%, respectively. Area under the curve was 0.84 (95% confidence intervals: 0.72-0.96; P<0.05). LR+ and LR- were 5.3 and 0.17, respectively. F-18-FDG-PET/CT revealed new metastatic foci in 5/52 patients (10%) and excluded suspicious lesions in 11/52 (21%). Analysis of PFS revealed F-18-FDG-PET/CT positivity to be associated with a worse cumulative survival rate over a 6 and 12-month period in comparison with F-18-FDG-PET/CT negativity (6-month PFS 95 vs. 67%, P<0.05; 12-month PFS 81 vs. 29%, P<0.05). A negative F-18-FDG-PET/CT result was associated with a significantly longer overall survival than a positive one (70 vs. 26% after 2 years, P<0.05). In addition, a positive F-18-FDG-PET/CT scan result and an maximum standardized uptake value (SUVmax) value more than 6 were significantly associated with an increased risk of disease progression (PET positivity hazard ratio=3.9, P=0.01; SUVmax>6h=4.2, P=0.02) and death (PET positivity hazard ratio=3.5, P=0.02; SUVmax>6h=3.7, P=0.01). Conclusion F-18-FDG-PET/CT showed high diagnostic accuracy for restaging process of PC, proving also its potential value in predicting clinical outcome after primary treatment.