Background: Systemic chemotherapy is the primary treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinomas (PDAC). More effective treatment optionsarehighly awaited. The aim of this study was to evaluate the toxicity and feasibility of triweekly gemcitabine/nab-paclitaxel/S-1 (GAS) chemotherapy in patients with locally advanced or metastatic PDAC, determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of S-1 in this regimen, and explore the preliminary efficacy. Methods: Eligible patients with locally advanced or metastatic PDAC received GAS chemotherapy on a 21-day cycle. Fixed-dose of nab-paclitaxel (125 mg/m²) and gemcitabine (1000 mg/m²) were given intravenously on days 1 and 8. Different doses of S-1 were given orally twice daily from day 1 to day 14 within a 3+3 dose escalation design. According to patients` body surface area, the dose-escalation design was as follows: patients with a body surface area of 1.25–1.5 m² received S-1 40 mg/d initially and the dose was increased to 60 mg or 80 mg. Patients with a body surface area of more than 1.5 m² received S-1 60 mg/d initially and the dose was increased to 80 mg or 100 mg. The primary endpoints were to evaluate the toxicity and determine the DLT and MTD of S-1. The secondary endpoint was to evaluate efficacy. Results: A total of 21 eligible patients were included. Due to the infrequence of patients with a body surface area of 1.25–1.5 m², only 2 patients were included in cohort of S-1 40 mg. The dose-escalation for patients in this group failed to be enrolled completely. For patients with a body surface area of more than 1.5 m², 3 DLTs in 7 patients were detected at cohort of S-1 100 mg (grade 3 thrombocytopenia with hemorrhage, grade 3 rash, and grade 3 mucositis/stomatitis). S-1 80 mg/d (body surface area: > 1.5 m²) was considered to be the MTD in GAS chemotherapy (21-day cycle). No grade 4 adverse events (AEs) or treatment-related deaths were observed. The most common occurring hematologic AE of any grade was anemia (38.1%). The most frequent nonhematologic AEs of any grade were peripheral neuropathy (38.1%), dyspepsia (23.8%), constipation (23.8%), and alopecia (23.8%). After 2 cycles of GAS chemotherapy, the objective response rate was 36.8% and the disease control rate was 94.7%. The median progression-free survival was 5.3 (95% CI, 4.6 to 6.0) months and the median overall survival was 10.3 (95% CI, 8.1 to 12.5) months. Conclusions: GAS chemotherapy (21-day cycle) with nab-paclitaxel 125 mg/m², gemcitabine 1000 mg/m², and S-1 80 mg/d (body surface area: > 1.5 m²) was detected with the acceptable toxicity and significant clinical control in patients with locally advanced or metastatic PDAC. It is valuable to conduct further phase II trials. Clinical trial information: ChiCTR1900027833.