Introduction: The percutaneous Hartel’s technique is a well-described approach to targeting lesions in the Meckel’s cave. It is used as the standard approach for all percutaneous trigeminal neuralgia procedures for accessing the Gasserian ganglion through the foramen ovale. It has also been described to biopsy lesions in the Meckel’s cave and cavernous sinus using fluoroscopic guidance however there were a significant number of non-diagnostic samples. No one to date has described a combined fluoroscopic and image-guided approach to improve safety and accuracy. Methods: The patient had a 3-month history of left-sided facial numbness and a left VIth palsy causing diplopia and a squint. The CT of the chest, abdomen and pelvis was unremarkable as were the serum tumour markers. We describe the novel approach of using a percutaneous biopsy needle to obtain a cytological sample of a Meckel’s cave lesion using a combination of X-ray and EM image-guidance with use of StealthStation® S8® System (Medtronic Sofamor Danek, Memphis, USA). The need for a craniotomy and its associated morbidity and technical challenges was therefore obviated. Results: The procedure was performed under general anaesthesia and eight core samples were sent to neuro-pathology for analysis. The lesion was histologically confirmed to be lymphoma and the patient subsequently received oncological treatment. The patient had no immediate or post-operative complications and the use of the aforementioned combined approach improved safety and accuracy of targeting the lesion in real time. Conclusion: A combined percutaneous fluoroscopic and image-guided approach to biopsy a Meckel’s cave lesion is recommended.