Progressive multifocal leukoencephalopathy (PML) caused by the polyomavirus JC is a well-recognised complication of AIDS. Purely infratentorial manifestations are rare. Introduction of highly active antiretroviral therapy (HAART) has been associated with a reduction in morbidity and an improvement in overall survival among HIV-infected individuals. Recently, several reports have described adverse events in patients with PML who begin HAART and show evidence for immune reconstitution. We describe the clinical course of two patients with PML with purely infratentorial manifestation, whose clinical course deteriorated despite the successful introduction of HAART. Possible underlying immunological mechanisms are discussed.