To evaluate the benefit of combined antiretroviral therapy including protease inhibitors (CART) on survival time and neurological progression in patients with AIDS-related progressive multifocal leukoencephalopathy (PML), 81 consecutive PML cases, collected between January 1990 and June 1998, were reviewed. Fifteen patients were neuropathologically proven. JC virus detection in CSF was positive in 59 patients. At PML diagnosis, median CD4 cell count was low (median, 35 cells/microL) and plasma HIV load, determined in 41 patients, was high (median, 4.8 log10 copies/ml). Following PML diagnosis, there was a significant difference (P<10(-4)) in survival between patients who were untreated or treated with nucleoside analogs (n=50, median: 80 days) and patients who were started early on CART (n=23, median: 246 days). A third group of eight patients who received CART late during the course of PML was considered separately. At the study endpoint, 18 of all the CART-treated patients (n=31) were still alive. Plasma HIV load was undetectable in 67% of them. The median increase in CD4 cell count was 112 cells/microL from CART onset. In contrast, no significant improvement in neurological status was observed. Our results demonstrate a benefit of CART on survival of AIDS-related PML patients and suggest the need for an early, specific anti-JC virus treatment to limit the neurological deterioration.