A 70-year-old woman with therapy-related acute myeloid leukaemia underwent a haploidentical umbilical cord stem cell transplant (SCT). Twenty-eight days later, she presented with altered mental status and diarrhoea. Bone marrow biopsy showed maturing trilineage haematopoiesis with no evidence of residual disease. There were scattered enlarged cells with large eosinophilic cytopathic intra-nuclear inclusion bodies and abundant foamy cytoplasm (image, haematoxylin and eosin). The inclusions were round, centrally situated, and surrounded by a clear halo. Immunohistochemical staining for cytomegalovirus (CMV), Epstein–Barr virus (EBV), BK virus, human herpesvirus 8, herpes simplex virus 1, herpes simplex virus 2 and parvovirus B19 was negative. Quantitative real-time polymerase chain reaction assays and serological tests for CMV, EBV, parvovirus B19, BK virus and Toxoplasma gondii were all unremarkable. However, very high copy numbers of human herpesvirus 6 (HHV-6) were detected (~300·103 copies/ml). The patient was started on foscarnet and subsequently switched to valganciclovir. As HHV-6 levels decreased to <200 copies/ml, the patient's clinical status quickly improved. Two follow-up bone marrow biopsies at 3 and 6 months post-SCT showed no intra-nuclear inclusions. Currently the patient remains in complete remission. Initial exposure to HHV-6 occurs in early childhood and results in a life-long latency in peripheral blood mononuclear cells, salivary glands and central nervous system. HHV-6 reactivation is noted in 30–70% of patients undergoing allogeneic SCT, typically 2–4 weeks after transplantation. Although HHV-6 reactivation is generally asymptomatic, it can present with fever, rash, diarrhoea, bone marrow suppression or encephalitis. HHV-6 infection is known to cause nuclear and/or cytoplasmic inclusion bodies in peripheral blood mononuclear cells and T-lymphocytes in skin. The exceptionally high copy numbers of HHV-6 and lack of laboratory or immunophenotypic evidence of any other infectious process lead us to postulate that the intra-nuclear inclusions represent evidence of HHV-6 infection. In summary, reactivation of HHV-6 should be considered in the differential diagnosis of cytopathic viral inclusions seen in a biopsy of a post-transplant patient. This diagnosis is clinically relevant, because HHV-6 reactivation has been associated with serious transplantation-related morbidity and mortality.