Purpose: To assess the safety and efficacy of irreversible electroporation (IRE) in the treatment of patients with inoperable hepatocellular carcinoma (HCC) who are ineligible for thermal ablative techniques. Materials and Methods: This retrospective study was approved by an ethics review board, and the requirement to obtain informed written consent was waived. From March 2012 to June 2015, 58 patients (median age, 65.4 years; range 41.6-90 years) with cirrhosis received IRE for the treatment of 75 HCC tumors. The median tumor diameter was 24 mm (range, 6-90 mm). IRE was selected because of tumor location (48 patients) or the patient's poor general condition (10 patients). Treatment response was assessed with magnetic resonance (MR) imaging 1 month after treatment and every 3 months thereafter. Overall local tumor progression-free survival (PFS) per nodule (including initial treatment failures) was assessed by using the Kaplan-Meier method. The marginal Cox proportional hazards model was used to assess the factors associated with overall local tumor PFS. Complications were recorded and graded according to the Clavien-Dindo classification. Results: Of 75 tumors, 58 (77.3%), 67 (89.3%), and 69 (92%) were completely ablated after one, two, and three IRE procedures, respectively. After a median follow-up of 9 months (range, 3 days to 31 months), the 6- and 12-month overall local tumor PFS rates for the 75 treated nodules were 87% (95% confidence interval [CI]: 77%, 93%) and 70% (95% CI: 56%, 81%), respectively. A preablative serum α-fetoprotein level higher than 200 ng/mL (hazard ratio: 9.94 [95% CI: 2.82, 35.06], P = .0004) was the only factor linked with overall local tumor PFS. Complications occurred in 11 of the 58 patients (19%) and were classified as grade I in three patients, grade II in five patients, grade IV in two patients, and grade V in one patient. The three (5.2%) complications classified as grade III or higher were liver failures occurring in patients with Child-Pugh class B disease; one led to death. Conclusion: IRE offers safe, complete ablation of HCC tumors in patients with contraindications to other commonly used ablative techniques.