Background: The aim of this retrospective study was to evaluate the efficacy of adjuvant hepatic arterial infusion chemotherapy (HAI) using high-dose 5-fluorouracil with systemic gemcitabine on prognosis of resected pancreatic cancer. Methods: Between January 2006 and April 2016, 298 patients underwent elective pancreatic resection for resectable or borderline resectable pancreatic cancer at Nara Medical University Hospital. Patients who received adjuvant HAI plus systemic gemcitabine after surgery (HAI group) were compared with those who received systemic chemotherapy alone (control group). Patients were propensity score matched for age, sex, ASA score, CA19-9, NCCN resectability status, neoadjuvant treatment, surgical procedure, portal vein invasion, T stage, N stage, and margin status. Results: 224 patients with resectable or borderline resectable pancreatic cancer were enrolled in this study. 151 patients in the HAI group and 73 patients in the control group were included. Propensity score matching analysis was used to identify 63 well-balanced patients in each group for overall survival comparison. The estimate overall survival (OS) for patients treated with HAI was longer than patients without HAI in both the whole cohort (median OS, 54 vs. 24 months, respectively; P< 0.001) or matched cohort (median OS, 58 vs. 26 months, respectively; P = 0.003). The liver was only recurrence site in which significant decrease was observed in the HAI group compared to the control group (P = 0.031). In the multivariate analysis, adjuvant chemotherapy without HAI were independently associated with worse outcome in the whole cohort. A total of 127 patients in the HAI group (84%) had completed the planned dose of HAI. The remaining 24 patients stopped treatment before the end of the planned cycle due to catheter-associated complications in 9 (6.0%) and development of liver abscess in 2 (1.3%). No treatment-related deaths occurred. Conclusions: The efficacy of hepatic arterial chemoinfusion as adjuvant treatment for resectable pancreatic cancer should be revisited.