Progressive multifocal leukoencephalopathy (PML) is a rare but usually fatal demyelinating disease of the central nervous system in patients who are immunocompromised. It is characterized by rapid neurological deterioration associated with progressive white matter changes on imaging and is confirmed by isolation of the causative virus in the cerebrospinal fluid or brain tissue. Currently there are no effective treatments for PML and outcomes remain poor even after reversal of the immunocompromised state. This case series describes three patients with different underlying pathologies and varying presentations who were all diagnosed with PML and referred to a palliative care service.