Abstract Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. Perfluorooctanoic acid (PFOA), a persistent environmental pollutant, has been shown to induce pancreatic acinar cell tumors in rats. Human epidemiologic studies have linked PFOA exposure to adverse chronic health effects including several types of cancer. Previously, we demonstrated that PFOA induces oxidative stress and focal ductal hyperplasia in the mouse pancreas. Here, we evaluated whether PFOA promotes pancreatic cancer using the LSL-KRasG12D;Pdx-1 Cre (KC) mouse model of pancreatic cancer. KC mice were exposed to 5 ppm PFOA in drinking water starting at 8 weeks of age and analyzed at 6 and 9 months of age. At the 6-month time point, PFOA exposure increased pancreatic intraepithelial neoplasia (PanIN) area by 58%, accompanied by a 2-fold increase in lesion number. Although PanIN area increased at 9 months, relative to 6 months, no treatment effect was observed. Collagen deposition was enhanced by PFOA at both the 6- and 9-month time points. PFOA also induced oxidative stress in the pancreas evidenced by elevated antioxidant activity of superoxide dismutase (Sod), catalase and thioredoxin reductase, and a ~3-fold increase in Sod1 mRNA and protein levels at 6 months. Although antioxidant activity was not enhanced by PFOA exposure at the 9-month time point, increased pancreatic oxidative damage was observed. Collectively, these results show that PFOA elicited temporal increases in PanIN lesion area and desmoplasia concomitant with the induction of oxidative stress, demonstrating that it functions to promote pancreatic cancer progression. We demonstrate that PFOA exposure elicits temporal increases in PanIN lesion area and desmoplasia concomitant with the induction of oxidative stress in the LSL-KRasG12D;Pdx-1Cre mouse model of pancreatic cancer, demonstrating that PFOA exposure acts at the promotion stage of carcinogenesis. Graphical Abstract Graphical Abstract