Purpose To (a) investigate the safety of percutaneous irreversible electroporation (IRE) for locally advanced pancreatic cancer and (b) evaluate the quality of life (QOL), pain perception, and efficacy in terms of time to local progression, event-free survival, and overall survival (OS). Materials and Methods The study was approved by the local review board (NL42888.029.13). All patients provided written informed consent for study participation, the ablation procedure, and data usage. Between January 2014 and June 2015, 25 patients with histologically proved locally advanced pancreatic cancer 5 cm or smaller (13 women, 12 men; median age, 61 years; age range, 41-78 years) were prospectively included to undergo percutaneous computed tomographic-guided IRE. Patients with a metallic biliary Wallstent, epilepsy, or ventricular arrhythmias were excluded. Kaplan-Meier estimates were used to investigate time to local progression, event-free survival, and OS. Safety was assessed on the basis of adverse events, which were graded according to the Common Terminology Criteria for Adverse Events. Pain perception and QOL were evaluated by using specific questionnaires. Results All patients underwent IRE. The median largest tumor diameter was 4.0 cm (range, 3.3-5.0 cm). After a median follow-up of 12 months (interquartile range: 7-16 months), median event-free survival after IRE was 8 months (95% confidence interval [CI]: 4 months, 12 months); the median time to local progression after IRE was 12 months (95% CI: 8 months, 16 months). The median OS was 11 months from IRE (95% CI: 9 months, 13 months) and 17 months from diagnosis (95% CI: 10 months, 24 months). There were 12 minor complications (grade I or II) and 11 major complications (nine grade III, two grade IV) in 10 patients. There were no deaths within 90 days after IRE. Conclusion Percutaneous IRE for locally advanced pancreatic cancer is generally well tolerated, although major adverse events can occur. Preliminary survival data are encouraging and support the setup of larger phase II and III clinical trials to assess the efficacy of IRE plus chemotherapy in the neoadjuvant and adjuvant or second-line setting compared with more widely adopted regimens such as chemotherapy and/or radiation therapy. (©) RSNA, 2016 Online supplemental material is available for this article.