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Human herpes virus-6 (HHV-6) encephalitis is one of the life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Early diagnosis and intervention are important for the prevention of poor prognosis and sequelae. Although hyponatremia is known to be associated with HHV-6 encephalitis, it is unclear whether the preceding hyponatremia is a useful hallmark for the diagnosis of HHV-6 encephalitis. We retrospectively reviewed 134 consecutive patients who underwent allo-HSCT at our institution and evaluated the relationship between HHV-6 encephalitis and hyponatremia. Interestingly, 7 (50%) of 14 patients who developed HHV-6 encephalitis presented hyponatremia within a week before the onset of HHV-6 encephalitis. On the other hand, only 14 (11.7%) out of 120 patients without HHV-6 encephalitis developed hyponatremia. Hyponatremia, treating as a time-dependent covariate, was significantly correlated with the incidence of HHV-6 encephalitis. Moreover, the diagnostic accuracy analysis showed that the coexistence of hyponatremia and central nerve system (CNS) dysfunction strongly suggests HHV-6 encephalitis. In conclusion, our study suggests the likelihood of HHV-6 encephalitis significantly increases in the patients with CNS dysfunction following hyponatremia after allo-HSCT and this combination may help in early diagnosis and intervention of HHV-6 encephalitis after allo-HSCT.