Our aim was to assess oncologic, safety, and quality of life-related outcomes of focal therapy with irreversible electroporation in men with localized prostate cancer. This was a single-center, phase II study. prostate cancer International Society of Urological Pathology grade 1-2, prostate specific antigen ≤15 ng/ml, ≤cT2b. Patients were selected based on multiparametric magnetic resonance imaging and transperineal systematic and targeted magnetic resonance imaging-ultrasound fusion-guided biopsy. Ablation of index lesions with safety margin was performed. Primary end point was cancer control, defined as the absence of any biopsy-proven tumor. A control transperineal biopsy was planned at 12 months and when suspected based on prostate specific antigen and/or multiparametric magnetic resonance imaging information. Quality of life was assessed using Expanded Prostate Cancer Index Composite Urinary Continence domain, International Index of Erectile Function, and International Prostate Symptom Score. From November 2014 to July 2021, 41 consecutive patients were included with a median follow-up of 36 months. Thirty patients (73%) had International Society of Urological Pathology grade 1 tumors, 10 (24%) grade 2, and 1 (2.4%) grade 3. Recurrence was observed in 16 of 41 (39%) of the whole cohort, and 16 of 33 (48.4%) who underwent biopsy. In-field recurrence was detected in 5 (15%) and out-of-field in 11 (33.3%). Ten of 41 (24.6%) including 3 of 5 (60%) with in-field recurrences had significant tumors (Gleason pattern 4-5; more than 1 core or any >5 mm involved). Median recurrence-free survival was 32 months (95% CI 6.7-57.2). Twenty-six patients (63.4%) were free from salvage treatment. All patients preserved urinary continence. Potency was maintained in 91.8%. Irreversible electroporation can achieve satisfactory 3-year in-field tumor control with excellent quality of life results in selected patients.