Background and Aims: In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naïve locally advanced pancreatic cancer (LAPC) received intravenous porfimer sodium followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser and illumination with a 630-nm light. A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel and gemcitabine were initiated 7 days after CT. Results: Twelve patients (mean age, 67 ± 6 years; 8 male) with tumors (mean diameter, 45.2 ± 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. No serious adverse events from PDT occurred. Conclusion: EUS-PDT for LAPC is technically feasible. Phase II studies are warranted.