BACKGROUND Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating illness caused by the JC virus, a polyomavirus that occurs in 4-5% of HIV-positive patients. Mortality is high, and no useful therapy has been identified. Highly active antiretroviral therapy (HAART) has been reported to be effective in halting progression of the disease in some, but not all, patients. Cidofovir has been shown to be active against polyomaviruses. OBJECTIVE To review data on the use of cidofovir to treat PML. METHODS English-language case reports and clinical studies were located through a literature search (MEDLINE and AIDSLINE, 1995-July 2000). METHODS Relevant case reports and studies describing the use of cidofovir for PML were reviewed. RESULTS Most case reports describing the use of cidofovir have shown that the drug is effective in the treatment of PML. Some patients were also receiving HAART concurrently; therefore, it is not clear which treatment modality had a greater impact on PML. However, cidofovir may be effective in patients whose disease has progressed despite HAART or who are-unable to tolerate these regimens. A pilot study of cidofovir for treating PML has completed enrollment, but preliminary results showed no benefit. CONCLUSIONS Cidofovir may be the most reasonable treatment option for PML in HIV-infected individuals who fail to improve with HAART or who are unable to tolerate these regimens. Patients who receive cidofovir should be monitored for renal and ocular toxicity.