Percutaneous ablative treatments in the kidney are now standard options for local cancer therapy. Multimodality image guidance, combining two 3D image sets, may improve procedural images and interventional strategies. We aimed to assess the value of intra-procedural cone beam computed tomography (CBCT) with magnetic resonance (MR) or CT imaging fusion technique in the guidance of percutaneous microwave ablation (MWA) of renal neoplasms. Fifteen patients (eight males, seven females, median age 65 years, median lesion size 20 mm) underwent percutaneous MWA for 15 renal tumors. All the procedures were performed in a dedicated angiography room setting; CBCT ablation planning capabilities included multimodality image fusion. Preoperative contrast-enhanced CT was available in 12 patients, whereas magnetic resonance imaging in the remaining. All patients were considered inoperable due to comorbidities, advanced age, and/or refusal to undergo surgery. Exclusion criteria were: tumors visible at unenhanced CBCT, metastatic disease, and uncorrected coagulopathy. Technical success and technical effectiveness were calculated. Procedural time, complications and recurrences were registered. MWA under CBCT-guidance with fusion technique was technically successful in 14 out of 15 cases (93%). The median procedural time was 45 min. No procedure-related complications were reported. No enhancing tissue was visualized in the area of ablation at 1-month follow-up. All 15 cases were recurrence-free at last follow-up assessment (median follow-up of 12 months); no cancer-specific deaths were registered. CBCT-CT/MR image fusion is technically feasible and safe in achieving correct targeting and complete ablation of renal lesions. This approach bears the potential to overcome most of the limitations of unenhanced CBCT guidance alone; larger series are needed to validate this technique.