Background: There is an unmet need for improved non-invasive markers to assess early treatment response in pancreatic ductal adenocarcinoma (PDAC). Assessing early treatment response using tumor size on anatomic imaging or serum carbohydrate antigen 19-9 (CA19-9) level is unreliable. In contrast, metabolic and functional imaging is a promising new tool that may differentiate responders from non-responders early on during therapy. Therefore, the objective of this pilot study was to explore the potential of integrated positron emission tomography-magnetic resonance imaging (PET-MRI) to provide imaging biomarkers of early (4 weeks post treatment initiation) response in patients with advanced PDAC. Methods: 13 patients with biopsy-proven locally advanced or metastatic PDAC underwent integrated 18F-fluorodeoxyglucose PET-MRI through the abdomen prior to, and again at 4 weeks post, treatment initiation. Patients also had computed tomography (CT) imaging of the chest, abdomen, and pelvis and serum CA19-9 levels measured, as per standard of care. Patients were classified as responders or non-responders according to RECIST (Response Evaluation Criteria In Solid Tumors) on delayed CT, at 8-12 weeks interval post treatment initiation. Changes in metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from PET, and apparent diffusion coefficient (ADC) from diffusion-weighted MRI at 4 weeks were compared between responders and non-responders. Results: Of the 13 patients, there were 7 responders (partial response by RECIST) and 6 non-responders (progressive or stable disease by RECIST). After 4 weeks of therapy, responders had a significantly greater decrease in MTV (p = 0.003) and TLG (p = 0.006) compared to non-responders. Responders also had a significantly greater increase in mean and minimum ADC (p = 0.004 and p = 0.024, respectively) compared to non-responders. Change in tumor size at 4 weeks was not significantly different between responders and non-responders (p = 0.11). Conclusions: Integrated PET-MRI can provide early assessment of treatment response in patients with advanced PDAC.