Central nervous system complications are common in stem cell transplant recipients, but selective involvement of the medial temporal area is unusual. The 5 patients reported here presented after stem cell transplantation with increased hippocampal T2 signal on magnetic resonance imaging and increased hippocampal glucose uptake on [F-18]fluorodeoxyglucose-positron emission tomography (FDG-PET) associated with short-term memory loss, insomnia, and temporal lobe electrographic seizure activity. The initial scalp electroencephalograms (EEGs) failed to detect seizure activity in these patients, although the memory dysfunction along with the magnetic resonance imaging and FDG-PET findings suggested subcortical seizure activity. However, extended EEG monitoring revealed repetitive temporal lobe electrographic seizure activity. Follow-up MRIs in 2 patients and postmortem findings on 1 patient suggested that hippocampal sclerosis had developed following the clinical syndrome. Cerebrospinal fluid studies revealed the presence of human herpesvirus 6, variant B, DNA in all of 3 patients who had lumbar punctures. Immunohistochemical staining for the P41 and P101 human herpesvirus 6 protein antigens showed numerous immunoreactive astrocytes and neurons in the hippocampus of 1 of the patients who died from other causes. Because of its subtle clinical presentation, this syndrome may be underrecognized, but can be diagnosed with appropriate magnetic resonance imaging techniques, EEG monitoring, and cerebrospinal fluid viral studies.