Despite extensive work-ups, some patients have been diagnosed with hemophagocytic lymphohistiocytosis (HLH) of unknown etiology. For HLH of unknown etiology, to investigate the clinical features and the factors that may affect the prognosis, we retrospectively reviewed the medical records of 94 patients hospitalized from January 2014 to December 2019. Survival times were evaluated until April 2020. For the 94 patients, the underlying causes of their diseases remained unclear at the end of the follow-up period, and the 1-, 3-, and 6-month survival rates, and the overall survival (OS) rates were 86.2%, 78.7%, 73.4%, and 70.2%, respectively. The multivariate analysis showed that the absence of an overall response or remission within 1 month after initial induction therapy (hazard ratio [HR], 11.914; 95% confidence interval [CI], 3.114-45.584; p < 0.001) and the refractory and relapsed HLH (HR, 16.003; 95% CI, 2.425-105.598; p = 0.004) were independently associated with adverse prognoses. The OR rate within 1 month occurred in 86.2% of the patients with doxorubicin-etoposide-methylprednisolone (DEP) regimen as initial induction treatments, while, that occurred in 58.46% of the patients with non-DEP regimens (p = 0.008). The OS rates did not differ between the patients with DEP regimens and non-DEP regimens (p = 0.252). These findings suggest that HLH of unknown etiology has relatively good OS rate and prognosis overall. Absence of an OR within 1 month after initial induction therapy and refractory and relapsed HLH were independently associated with adverse prognoses. The DEP regimen indeed could improve the OR rate, but it failed to show an OS benefit.