Background Neoadjuvant chemotherapy (NAC) represents a promising alternative to pancreatic ductal adenocarcinoma (PDAC) planned resection, but the survival impact remains undefined. To assess the feasibility and survival outcomes of NAC with gemcitabine and S1 (GS) for PDAC planned resection by prospective study. Methods Patients with resectable or borderline resectable PDAC received 2 cycles of NAC-GS and were offered curative resection followed by gemcitabine adjuvant. The primary endpoint was 2-year overall survival (OS). Adverse events during NAC, radiological and tumor marker responses, resection rate, and surgical safety were evaluated as secondary endpoints (UMIN000004148). Results We enrolled 104 patients between 2010 and 2012, with 101 patients treated using NAC-GS as the full analysis set (FAS). Of the 101 patients, 88% received the planned 2 cycles of NAC. Grade 3 neutropenia was common (35%). Radiological partial response and decreased carbohydrate antigen 19-9 concentration (> 50% decrease) were noted in 13% and 41%, respectively. R0/1 resections with M0 were performed in 65 patients without surgical mortality. Of the 65 patients, 44 received planned gemcitabine adjuvant for 6 months as the on-protocol cohort. The primary endpoint for the 2-year OS rate was 55.9% in the FAS ( n  = 101) and 74.6% in the on-protocol cohort ( n  = 44). Conclusions NAC-GS was feasible and actively prolonged survival following PDAC planned resection. Randomized control trials are needed to further clarify the survival benefit of NAC-GS in addition to surgery followed by adjuvant therapy.