We report the case of a male heart transplant recipient who developed acute antibody-mediated rejection and was treated with 5 weeks of a rituximab-containing regimen. Two months later he presented with progressive motor and cognitive impairments and was diagnosed with progressive multifocal leukoencephalopathy (PML). He was treated with reduction of his immunosuppressive medications, mirtazapine, IVIG and plasmapheresis. He died within weeks. We reviewed the current literature on PML and its association with immunosuppression, highlighting its impact in the setting of solid organ transplantation and considering the potential effect of newer biologic drugs on the incidence of this devastating disease in the transplant population.