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Abstract: Gianotti–Crosti syndrome (GCS) is known to be associated with hepatitis B and Epstein–Barr virus (EBV) infections. Apart from a single case report based on serology alone, there are no published data on an association between GCS and human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) primary infections or reactivations. Our aim was to investigate the association between GCS and HHV-6 and HHV-7 infections. Ten patients diagnosed with GCS at a primary care practice over an 18-month period were recruited. Controls were age- and sex-matched patients with unrelated symptoms requiring venepuncture for other indications. Blood specimens were collected from patients and controls at presentation, and from patients 4 weeks later. Virologic evidence of HHV-6 and HHV-7 infection was sought in peripheral blood leukocytes and plasma using polymerase chain reaction (PCR) for viral DNA, reverse transcriptase polymerase chain reaction (RT-PCR) for HHV-6 U91 mRNA transcripts, and serology. Serology for EBV and hepatitis B virus was done. In contrast to the 10 controls, 2 patients (both infants) with clinically diagnosed GCS had evidence of active HHV-6 infection. This was demonstrated by detection of viral DNA in the absence of antibody in the acute plasma specimens and HHV-6 DNA viral loads of more than 5.3 log10 genome copies/5 μl in the whole blood specimens, a profile previously shown to be diagnostic of recent primary HHV-6 infection. None of the patients had evidence of recent EBV or hepatitis B infection. We conclude that primary HHV-6 infection may be associated with GCS in some infants.