This study investigated factors associated with the development of human herpesvirus (HHV)-6 encephalitis. Among 111 enrolled subjects, 12 patients developed central nervous system (CNS) dysfunction. CNS dysfunction in four patients was found to have no association with HHV-6. The remaining eight patients displayed HHV-6 encephalitis (n=3), limbic encephalitis (HHV-6 DNA in cerebrospinal fluid was not examined; n=3) or CNS dysfunction because of an unidentified cause (n=2). Real-time PCR showed CNS dysfunction in the latter eight patients, which developed concomitant with the appearance of high plasma levels of HHV-6 DNA (> or =10(4) copies/ml). Overall, eight of the 24 patients with high-level HHV-6 DNA developed CNS dysfunction, whereas no patients developed CNS dysfunction potentially associated with HHV-6 infection if peak HHV-6 DNA was <10(4) copies/ml. We next analyzed plasma concentrations of IL-6, IL-10 and tumor necrosis factor-alpha among patients who displayed high-level plasma HHV-6 DNA and found elevated IL-6 concentrations preceding HHV-6 infection in patients who developed CNS dysfunction. (Mean+/-s.d.: 865.7+/-1036.3 pg/ml in patients with CNS dysfunction; 56.5+/-192.9 pg/ml in others; P=0.01). These results suggest that high-level HHV-6 load is necessary for the development of HHV-6 encephalitis, and systemic inflammatory conditions before HHV-6 infection form the preparatory conditions for progression to encephalopathy.