Irreversible electroporation (IRE) is considered predominantly as a non-thermal ablative technique that uses electrical fields to permeabilize cell membranes and lead to cell death. In this study, we evaluated the efficacy of IRE in the rabbit VX2 breast cancer model. Thirty-five female New Zealand white rabbits were inoculated against VX2 breast cancer cells. The rabbits were randomly divided into two groups: a control group of 15 rabbits and an IRE treatment group of 20 rabbits. Treatment and treatment outcome were evaluated by computerized tomography (CT) scan (plain or contrast enhanced), tumor growth curves and pathological examination including H& E, TUNEL, PCNA and CD31 staining. All rabbits in the IRE treatment group experienced successful IRE without obvious complications except for thoracic major muscle injury. A focused, complete and well-defined ablation zone where tumor cells have been thoroughly eradicated was detected by H& E staining, along with increasing TUNEL staining. The expression of PCNA and CD31 was down-regulated at the periphery of the ablation region. As of the last follow-up, 10 rabbits (67%) in IRE group demonstrated disease is under control; 2 rabbits (13%) are in stable condition; 3 rabbits (20%) suffered from disease progression; the remaining 5 rabbits were sacrificed for pathological examination halfway through the study. Overall, the efficacy of IRE was demonstrated by the creation of a complete ablation region, with increased apoptosis in the ablation zone and decreased proliferation and microvessel density of tumor tissue at the periphery. IRE is a promising local treatment for breast cancer.