Purpose: To compare survival after CT-guided percutaneous irreversible electroporation (IRE) and folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy versus FOLFIRINOX only in patients with locally advanced pancreatic cancer (LAPC). Materials and Methods: A post hoc comparison was performed of data derived from a prospective IRE-FOLFIRINOX cohort and a retrospective FOLFIRINOX-only cohort. All patients received a minimum of 3 cycles of FOLFIRINOX for LAPC and were considered eligible for CT-guided percutaneous IRE. Endpoints included overall survival (OS), local and distant progression-free survival, and time to progression (TTP) and were compared using stratified Kaplan-Meier analysis. Patients who received > 8 cycles of FOLFIRINOX before IRE and who had tumors > 6 cm in the FOLFIRINOX-only group were excluded. Results: Of 103 patients with a diagnosis of LAPC, 52 were deemed eligible (n = 30 IRE-FOLFIRINOX and n = 22 FOLFIRINOX-only). Patients in the FOLFIRINOX-only arm had larger tumors (53 mm ± 19 vs 38 mm ± 7, P = .340), had more locoregional lymph node metastases (23% vs 7%, P = .622), and more often received radiotherapy (7 patients vs 2 patients, P = .027); all other baseline characteristics were comparable. Median OS was 17.0 months (range, 5–35 mo; SD = 6) for IRE-FOLFIRINOX versus 12.4 months (range, 3–22 mo; SD = 6) for FOLFIRINOX-only (P = .038). After sensitivity analyses, median OS was 17.2 months (range, 6–27 mo; SD = 6) versus 12.4 months (range, 7–32 mo; SD = 10) (P = .05). Median TTP was longer in the IRE-FOLFIRINOX group: 14.2 months (range, 5–25 mo; SD = 4) versus 5.2 months (range, 2–22; SD = 6) (P = .0001). Conclusions: In patients with LAPC after FOLFIRINOX chemotherapy, CT-guided percutaneous IRE may improve OS and TTP. This study may facilitate the design of randomized controlled trials to compare survival after IRE-FOLRINOX versus FOLFIRINOX-only.