Hirst’s encephalitis is a severe disease characterized by an acute onset and rapidly progressive inflammation with symmetrical multifocal lesions of the brain, less often the cerebellum, brain stem, or spinal cord, manifested by white matter necrosis and numerous hemorrhages. Cases of Hirst’s encephalitis are quite rare; by 2014, about 100 cases of the disease have been described in the literature. The mortality rate for this disease reaches 70%. Its etiology remains unclear, and in most cases, the diagnosis is made heuristically, based on the similarity of clinical manifestations in a particular patient with the “classical” descriptions available in the literature. The article presents two clinical cases of Hirst’s encephalitis. In the first case, the disease debuted at the age of 14 with mental disorders, manifested by panencephalitis, depression of consciousness, and epileptic seizures. Against the background of aggressive therapy, it was possible to achieve a positive result, however, with an outcome in gross neurological and cognitive deficits. In the second case, the disease debuted at the age of 49 with loss of consciousness, manifested itself as resistant status epilepticus and multifocal inflammatory lesions of the white matter of both brain hemispheres with foci of hemorrhagic impregnation. Despite intensive therapy, this case was fatal. In conclusion, a description of the approaches to the diagnosis and treatment of Hirst’s encephalitis based on the data of modern literature is presented.