Progressive multifocal leukoencephalopathy (PML) is a rare, frequently fatal, infectious complication occurring in immunocompromised patients. PML has been well-reported in patients with chronic inflammatory rheumatic diseases taking immunosuppressive drugs. Awareness of the occurrence of PML in patients with rheumatic diseases has recently been highlighted by the occurrence of several cases of PML following administration of natalizumab and rituximab, biologic agents which have been used for the treatment of rheumatic diseases. Nearly two thirds of cases of PML in patients with rheumatic diseases reported in the medical literature occurred in patients with systemic lupus erythematosus (SLE). Over 40% of PML cases in SLE occurred in patients who had had minimal iatrogenic immunosuppression, suggesting that SLE itself may predispose to PML. The mechanism of this putative predisposition of SLE patients to the development of PML remains unexplained.