The aim of this study was to evaluate the role of human herpesvirus-6 (HHV-6) in the development of primary Sjögren's syndrome (PSS). Serum HHV-6 antibody levels, as measured by immunofluorescence assay (IFA) and the prevalence of HHV-6 DNA in peripheral blood mononuclear cells (PBMCs) determined by polymerase chain reaction (PCR), were studied in 49 PSS patients and 50 control subjects, all in-patients in the University Hospital Internal Medicine ward, Limoges, France. In addition, portions of labial salivary gland were obtained from 34 patients and 15 controls, the presence of viral DNA being detected by the same PCR technique. The results were then compared with clinical observations of systemic disease manifestations in patients and a histological study of salivary gland involvement. No significant difference in HHV-6 seroprevalence was found between control subjects (50.0%) and patients (63.3%) nor was there any statistically significant difference between patient and control groups for total viral DNA in PBMCs (22.4%, 12.0%) and salivary glands (8.8%, 6.6%). Analysis of clinical and histological data revealed no detectable correlation between disease severity and viral involvement. Tests for HHV-6A and HHV-6B proved positive in patient and control groups, HHV-6B being the most frequently encountered type in both groups. In conclusion, the results of this large-scale trial does not confirm the suspected direct role of HHV-6 in the etiology of PSS.