We report herein the case of a 37-year-old man who developed probable progressive multifocal leukoencephalopathy (PML) following an umbilical cord blood transplant. The patient showed favorable clinical, neuroradiological and virological responses after treatment with mefloquine, an anti-malarial drug. Mefloquine may offer some benefits as a treatment for PML in patients with or without human immunodeficiency virus type-1 infection. This report highlights the need to gather sufficient data to confirm the efficacy of mefloquine against this devastating viral disease of the central nervous system.