Background: Pancreatic cancer is a disastrous malignancy characterized by the dense fibrous stroma, elevating interstitial pressure and impairing perfusion of chemotherapeutics. Pirfenidone (PFD) is an oral antifibrotic agent, which might reduce the degree of fibrosis of pancreatic cancer and increase drug delivery. Thus, we aimed to evaluate the efficacy and safety of pirfenidone (PFD) plus nab-paclitaxel and gemcitabine (AG) for patients with metastatic pancreatic cancer. Methods: In this two-stage single-arm phase II trial, treatment-naïve patients with metastatic pancreatic cancer received oral PFD, 200 mg three times daily in the first week and 400 mg three times daily thereafter, in combination with intravenously administered gemcitabine 1000 mg/m2 and nab-paclitaxel 120 mg/m2 on days 1,8 of each 21-day cycle. The primary endpoint was overall response rate (ORR). A total of 33 patients were required based on the assumption of an expected ORR of 45%, with an α-error of 5% (one-sided) and a β-error of 20%. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: We enrolled 33 patients from October 2020 to February 2023, with median age of 61years (IQR 53-65), 21(63.6%) male and 12(36.4%) female. Metastatic sites included the liver (32cases), lung(7cases) and peritoneum (11cases). The last one patient was enrolled on February 24, 2023 and the deadline of follow up was Jan 25, 2024, with only one was unevaluable. The ORR was 50.0% (95% CI 33.6%-66.4%) and the DCR was 93.8%(95%CI 79.9%-98.9%). The median PFS was 4.9 months (95% CI 3.9-5.9) and the median OS was 9.1 months (95% CI 7.8-10.4). Among all cases of 25 with elevated CA19-9 at diagnosis, 56% patients experienced a decrease in CA19-9 levels of more than 50%. Grade 3-4 toxicities were observed in 11 (34.4%) patients, with leukopenia (7[21.9%]), anemia (5[15.6%]) and elevated AST level (4[12.5%]). No treatment-related deaths occurred. Conclusions: Adding PFD to AG showed promising ORR and DCR and an acceptable adverse event in patients with metastatic pancreatic cancer. Clinical trial information: ChiCTR2000034397.