Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the John Cunningham (JC) virus, a DNA papovavirus. It is usually associated with conditions causing profound immunodeficiency, classically seen in patients with HIV/AIDS. Since its first description in 1958, PML has also been associated with various lymphoproliferative malignancies, including chronic lymphocytic leukemia (CLL). With the use of newer chemotherapeutic agents such as the purine analogue fludarabine and various monoclonal antibodies in the treatment of CLL, more cases of PML are being described. In this article, we describe 3 patients encountered in our clinical practice having CLL and PML infection. All three patients had received fludarabine and rituximab at some point during the course of their chemotherapy. We provide these cases with a review of the literature.