Background: Gemcitabine has been approved as the standard chemotherapy for advanced pancreatic cancer since 1996. FOLFIRINOX significantly improved ORR and OS than GEM single-agent, but the significant increase of grade 3/4 adverse reactions, limited its wide application. The FDA approved nab-Paclitaxel for advanced pancreatic cancer in 2013. S-1 has demonstrated potential value in the treatment of advanced pancreatic cancer in Japan. We conducted a single arm, prospective, phase II study on the first-line treatment of advanced pancreatic cancer with nab-Paclitaxel and S-1 to investigate the efficacy and safety. Methods: Patients with untreated metastatic pancreatic cancer were treated with nab-Paclitaxel and S-1. Nab-Paclitaxel was administered intravenously on days 1 and 8 at 120mg/m², S-1 of 120mg (the surface area≥1.5m²), 100mg (the surface area≥1.25m²-1.5m²) and 80mg (the surface area <1.25m²) was given 2 times daily on days 1-14, for every 3 weeks. Patients who achieved overall objective response and stable disease after 6 cycles therapy were given S-1 maintenance treatment until disease progression or unacceptable toxicity. The primary objective was objective response rate (ORR) according to RECIST v1.1 criteria, and the secondary objectives were disease control rate (DCR), progress-free survival (PFS), overall survival (OS) and safety. Results: Between 12/2014 and 07/2017, 32 patients were entered in this monocentric phase II trial. The ORR in intention to-treat (ITT) population (N = 32) was 53.1%, the disease control rate (DCR) was 87.5%. In the 30 evaluable patient population, the ORR and DCR were 56.7%, 93.3%. In 29 patients(90.6%)with elevated carbohydrate antigen 19-9 (CA19-9) at baseline,15 patients (52.3%) had ≥ 50% decline from baseline CA19-9. The median follow-up time was 12 months (range 6-26), the median PFS was 6.2 months, the median OS was 13.6 months. The incidence of grade 3/4 neutropenia was 27.6%. The incidence of other grade 3 adverse was 13.9%. Conclusions: Nab-paclitaxel and S-1 showed encouraging ORR, OS and manageable toxicities, which is an effective alternative treatment regimen for advanced pancreatic cancer.