We report the intraoperative ultrasound findings in a male patient with history of stage IVb mantle cell lymphoma who developed new-onset personality changes and gait instability. Brain imaging revealed an extensive right frontal white matter lesion with subtle multifocal spreading. Given the absence of contrast enhancement on MRI and considering the high-dose steroid therapy administered, an open biopsy was performed due to suspicion of cerebral lymphoma. During procedure, intraoperative ultrasound with and without microbubble contrast was carried out, demonstrating distinct echotexture features, determining the site of biopsy. The histological analysis led to a diagnosis of progressive multifocal leukoencephalopathy (PML). To the best of our knowledge, this may represent one of the first descriptions of intraoperative ultrasound characteristics in PML.