This chapter discusses the clinical manifestations, pathology, epidemiology, and etiology of encephalitis lethargica. Clinically, encephalitis lethargica was characterized by diffuse involvement of the brain and spinal cord, producing practically the entire range of the signs and symptoms of neurological disease. The main pathological findings during the acute encephalitic illness were a diffuse inflammatory reaction in the meninges and around the blood vessels of the brain and the spinal cord. Degenerative changes were found in the neurones, especially in the brainstem, basal ganglia, and cerebellum, but also including the cortex and the subcortical white matter. Encephalitis lethargica was generally distributed by age, sex, race, occupation, education, economic status, and geographic location. A large proportion of individual encephalitis lethargica cases during the early years of the pandemic had had clinical influenza. Later, as influenza and encephalitis occurrence patterns shifted from massive epidemic to sporadic endemic, the relationship between these two diseases became progressively obscured.