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BACKGROUND: Delayed or decreased enhancement characteristics on computed tomography (CT) in patients with pancreatic fibrosis have been described. However, studies comparing clinical outcomes following pancreatoduodenectomy (PD) to preoperative CT enhancement characteristics are lacking. AIM: To study the ability of dual-phase CT to assess pancreatic fibrosis and to predict the risk of developing a pancreatic anastomotic failure (PAF) following PD.METHODS: Review of 157 consecutive patients with preoperative dual-phase CT between 2004 and 2009. Pancreatic CT attenuation upstream from the tumor was measured in the pancreatic and hepatic imaging phases. The ratio of the mean CT attenuation value of the pancreas in the hepatic (late) and pancreatic (early) phase was calculated; L/E ratio and histological grade of pancreatic fibrosis assessed by Masson trichrome immunostaining were then correlated with the development of a clinically-relevant PAF and other clinical parameters. Results: A clinically-relevant PAF was found in 21 patients (13.4%) with a morbidity rate of 39.5%. No postoperative death was observed. The PAF group showed maximum enhancement in the pancreatic and washout in the hepatic CT phase, while the control group showed a delayed enhancement pattern. Degree of pancreatic fibrosis and L/E ratio were significantly lower for the PAF group than the control group (21.0 ± 17.9 vs. 40.4 ± 29.8; P < 0.0001 and 0.86 ± 0.14 vs. 1.09 ± 0.24; P < 0.0001); fewer PAF patients showed an atrophic histological pattern (14% vs. 39%; P = 0.046). The L/E ratio was positively correlated with pancreatic fibrosis. Pancreatic fibrosis and L/E ratio increased with larger duct size (P < 0.001), the presence of diabetes (P < 0.05), and the surgeon’s assessment of pancreas firmness (P < 0.001). In multivariate analyses L/E ratio and BMI were significant predictors for the development of a clinically-relevant PAF; a 0.1 unit increase of L/E ratio decreased the odds of a PAF by 54%.CONCLUSIONS: Pancreatic CT enhancement characteristics quantified by the L/E ratio can accurately assess the histological grade of pancreatic fibrosis and are a powerful tool to predict the risk of developing a clinically-relevant PAF following PD. L/E ratio and pancreatic fibrosis are further associated with pancreatic texture, pancreatic duct size, and the presence of diabetes. This information may be helpful in guiding pre- and postoperative patient management.