Background: Despite recent progress of adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), its survival remains limited. We conducted a randomized controlled trial to compare neoadjuvant chemotherapy (NAC) with upfront surgery (UP-S) for patients with resectable PDAC. Methods: Patients with resectable PDAC, all confirmed cytologically or histologically were enrolled. Patients received 2 cycles of gemcitabine and S-1 regimen (GS) followed by surgery (NAC) or UP-S after randomization (1:1). Patients in both arms received adjuvant chemotherapy using S-1 for 6 months after surgical resection. The primary endpoint was overall survival (OS); secondary endpoints included adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases, and tumor marker kinetics. Results: A total 362 patients were randomly assigned to NAC-GS (n=182) or UP-S (n=180) for 3 years (2013-16). The median OS was 36.7 months in NAC-GS and 26.6 months in UP-S; HR 0.72 (p=0.015, stratified log-rank test) at 2.5 year after final enrollment. Crude resection rate for NAC and UP-S were 77%, 72% respectively. There was no operative mortality in both groups. Although G3/4 adverse events were observed frequently (73%) during NAC, no significant difference for both groups was observed for perioperative outcomes including blood loss, operation time, R0 resection rate and post-operative morbidity. Significant decrease of pathological nodal metastases in NAC was noted compared to those in UP-S by pathological evaluation for resected patients(p<0.01). Although significant decrease of viable tumor cells was observed in primary tumor after NAC compared to UP-S (p<0.01), Evans IIb or more was found in only 14 % of resected patients in NAC. Hepatic recurrence after surgery was significantly reduced in NAC (30.0%) compared to UP-S (47.5%) in observed period. Conclusions: The strategy of NAC showed significant longer survival compared to that of UP-S with acceptable feasibility. The effect of NAC might imply the control of subdiagnostic liver metastases before surgery for resectable PDAC. Clinical trial information: UMIN000009634.