Background Patients with locally advanced pancreatic cancer have a dismal prognosis, with a median overall survival (OS) of 12-14 months with systemic therapies. Irreversible electroporation (IRE), a nonthermal ablative technique, may prolong survival of patients with locally advanced pancreatic cancer. Purpose To investigate the safety and efficacy of percutaneous IRE for locally advanced pancreatic cancer and locally recurring pancreatic cancer in a prospective phase II trial. Materials and Methods Between December 2012 and September 2017, participants with locally advanced pancreatic cancer or postresection local recurrence were prospectively treated with percutaneous CT-guided IRE (ClinicalTrials.gov identifier: NCT01939665). The primary end point was median OS from diagnosis. The target median OS was 11.6 months for participants receiving no induction chemotherapy or gemcitabine-based induction chemotherapy and 14.9 months for those receiving induction 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Results Fifty participants (25 men and 25 women; median age, 61 years [interquartile range, 56-69 years]; 40 with locally advanced pancreatic cancer and 10 with local recurrence) were included. Median OS measured by using the Kaplan-Meier method was 17 months from diagnosis of locally advanced pancreatic cancer (95% confidence interval [CI]: 15 months, 19 months) and 10 months from IRE (95% CI: 8 months, 11 months). In the locally advanced pancreatic cancer group, 18 participants received no therapy or gemcitabine-based induction chemotherapy and 22 received FOLFIRINOX. The median OS from diagnosis was 17 months for both groups (95% CI: 7 months, 28 months and 15 months, 18 months, respectively; P = .26). For participants with postresection local recurrence, the median OS was 16 months from diagnosis of recurrence (95% CI: 11 months, 22 months) and 9 months from IRE (95% CI: 2 months, 16 months). After IRE, local recurrence developed in 23 of the 50 participants (46%). Tumor volume of 37 cm3 or greater (hazard ratio [HR], 2.9; P = .02), pre-IRE carbohydrate antigen 19-9 (CA 19-9) level of 2000 U/mL or greater (HR, 12.1; P = .001), and decrease in CA 19-9 level of 50% or less 3 months after IRE (HR, 3.1; P = .01) were predictors of worse survival. Fourteen minor and 21 major complications occurred in 29 of the 50 participants (58%). Two participants died less than 90 days after IRE; one of these deaths was likely related to IRE. Conclusion The target median overall survival with CT-guided percutaneous irreversible electroporation was exceeded in participants with locally advanced pancreatic cancer (17 months) and those with local recurrence (16 months). © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Goldberg in this issue.