After the introduction of highly active antiretroviral therapy (HAART), the incidence of many acquired immunodeficiency syndrome (AIDS)-related opportunistic infections, but not of progressive multifocal leukoencephalopathy (PML), has been dramatically decreased. However, it has been shown that about 50% of the HAART-treated PML patients had a significantly prolonged (>6 months) survival time, in comparison to the short (<6 months) survival time of the classical form of PML. In order to verify if a particular genotype or genomic rearrangements of JC virus (JCV) could affect the clinical course of PML, the authors performed nucleotide sequencing of 25 virion protein (VP1) and 18 transcriptional control region (TCR) DNA amplified in the cerebrospinal fluid (CSF) of HAART-untreated PML patients, of 17 HAART-treated PML patients, and in the urine of 23 healthy individuals. In nontreated PML patients, 52% and 44% of amplified JCV were respectively type 1 and type 2, whereas in HAART-treated PML patients, 59% of the amplified JCV were type 1, 23% type 2, and 18% type 4, without differences between long and short survivors. In both groups, the amplified TCR had unique and extensive rearrangements, whereas archetype TCR without rearrangements was detected in all the healthy subjects and in the CSF of two long-survivor PML patients. The data obtained indicate that the introduction of HAART has induced changes in JCV genotype distribution and probably reduced the rate of rearrangements of TCR region among PML patients.