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Human herpesvirus type 6 (HHV-6) has been shown to infect almost all children by 4 years of age. Primary infection causes an undifferentiated febrile illness, with approximately 30% of children exhibiting the classic clinical manifestations of exanthem subitum. Even with typical clinical presentation, exanthem subitum is frequently misdiagnosed as measles or rubella. Our aim was to describe the frequency and clinical manifestations of HHV-6 infection in children less than 4 years of age enrolled in a study designed to define the etiology of rash diseases.The study was conducted between January 1998 and December 2006 at a general hospital and a large primary health care unit from Niterói, Rio de Janeiro, Brazil. Sera from 223 children, in whom measles, rubella, dengue fever, and parvovirus B19 infections were excluded, were studied for anti-HHV-6 antibodies using an indirect immunofluorescence test. Demographic and clinical data of those patients were described.Ninety-seven (43.5%) of the children had evidence of primary HHV-6 infection. The age of onset peaked at 6–11 months and 75% of the HHV-6 infection occurred in children between 6 and 17 months. Only 21% of the HHV-6 cases had a typical roseola-like illness and 73% and 46%, respectively, fulfilled the clinical criteria of measles and rubella suspected case.Our study confirms the importance of HHV-6 infection in young children and highlights the difficulties of diagnosing a rash illness on clinical grounds alone.