To evaluate the association of progressive multifocal leukoencephalopathy (PML) with immunosuppressive therapy for autoimmune rheumatic diseases (ARDs). A Freedom of Information Act request was submitted for all cases of PML within the Food and Drug Administration Adverse Event Reporting System database. ARD cases were selected for further analysis. A total of 34 confirmed cases of PML in the setting of ARDs were identified: 17 had systemic lupus erythematosus, 10 had rheumatoid arthritis, 4 had vasculitis, and 3 had dermatomyositis. Fifteen of these patients were treated with one or more biologic agents: 14 received rituximab (RTX), 6 received anti-tumor necrosis factor (anti-TNF) therapy (5 treated with anti-TNF agent prior to RTX). Four RTX-treated patients were not receiving additional immunosuppressive therapy at the time of PML onset, other than an antimalarial drug and/or low-dose glucocorticoids; all others who were receiving a biologic agent were also receiving one or more synthetic disease-modifying agents. All but 1 patient receiving a biologic agent had at least 1 potential confounding factor for the diagnosis of PML. The remaining 19 confirmed cases of PML among ARD patients were treated with synthetic disease-modifying antirheumatic drugs only, 14 of whom had received an alkylating agent. PML has been reported in patients with ARD treated with various immunosuppressive agents. The limitations of this study preclude definitive attribution of causality. While the paucity of confirmed cases recently exposed to anti-TNF therapy suggests a causal relationship is unlikely, a specific signal is emerging with regard to rituximab and PML. Although this is a rare adverse event associated with RTX therapy, the devastating nature of PML mandates continued vigilance, particularly in patients with current or prior exposure to an alkylating agent. Copyright © 2012 by the American College of Rheumatology.