Background Irreversible electroporation (IRE) is a nonthermal ablative method based on the formation of nanoscale defects in cell membranes leading to cell death. Clinical experience with the technique for treatment of prostate cancer remains limited. Purpose To evaluate urogenital toxicity and oncologic outcome of MRI-transrectal US fusion-guided IRE of localized prostate cancer. Materials and Methods In this prospective study, men with biopsy-proven, treatment-naive, low- to intermediate-risk prostate cancer (prostate-specific antigen [PSA], ≤15 ng/mL; Gleason score, ≤3 + 4; clinical stage, ≤T2c; lesion size at multiparametric MRI, ≤20 mm) underwent focal MRI/transrectal US fusion-guided IRE between July 2014 and July 2017. Primary end point was the urogenital toxicity profile of focal IRE by using participant-reported questionnaires. Secondary end points were biochemical, histologic, and imaging measures of oncologic control. Analyses were performed by using nonparametric and χ2 test statistics. Results Thirty men were included (median age, 65.5 years); mean PSA level was 8.65 ng/mL and mean tumor size was 13.5 mm. One grade III adverse event (urethral stricture) was recorded. The proportion of men with erection sufficient for penetration was 83.3% (25 of 30) at baseline and 79.3% (23 of 29; P > .99) at 12 months. Leak-free and pad-free continence rate was 90% (27 of 30) at baseline and 86.2% (25 of 29; P > .99) at 12 months. Urogenital function remained stable at 12 months according to changes in the modified International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms, or ICIQ-MLUTS, and the International Index of Erectile Function, or IIEF-5, questionnaires (P = .58 and P = .07, respectively). PSA level decreased from a baseline median value of 8.65 ng/mL (interquartile range, 5-11.4 ng/mL) to 2.35 ng/mL (interquartile range, 1-3.4 ng/mL) at 12 months (P < .001). At 6 months, 28 of 30 participants underwent posttreatment biopsy. The rate of in-field treatment failure was 17.9% (five of 28) as determined with multiparametric prostate MRI and targeted biopsies at 6 months. Conclusion After a median follow-up of 20 months, focal irreversible electroporation of localized prostate cancer was associated with low urogenital toxicity and promising oncologic outcomes. © RSNA, 2019 Online supplemental material is available for this article.