Japanese encephalitis (JE) is numerically the most important global cause of encephalitis and so far confirmed to have caused major epidemics in India. Most of the reported studies have been in children. This largest study involving only adults, belonging to four epidemics, is being reported from Gorakhpur. The aim of this study is to detail the acute clinical profile (not viral) outcome and to classify the sequelae at discharge. This prospective study involved 1,282 adult patients initially diagnosed as JE admitted during the epidemics of 1978, 1980, 1988, and 1989, on identical clinical presentation and CSF examination. In the meantime, the diagnosis of JE was confirmed by serological and/or virological studies in only a representative number of samples (649 of 1,282 cases). Eighty-three left against medical advice (LAMA) at various stages, so 1,199 of 1,282 were available for the study. Peak incidence of [1,061 of 1,282 (83%)] of clinically suspected cases was from September 15 to November 2. Serum IgM and IgG were positive in high titers in 50.87% (330 of 649) and IgM positive in CSF in 88.75% (109 of 123) of the cases. JE virus could be isolated from CSF and brain tissue in 5 of 5 and 4 of 5 samples, respectively. Altered sensorium (AS) in (96%), convulsions (86%), and headache (85%) were the main symptoms for hospitalization by the third day of the onset. Other neurological features included hyperkinetic movements in 593 of 1,282 (46%)-choreoathetoid in 490 (83%) and bizarre, ill-defined in 103 (17%). The features of brain stem involvement consisted of opsoclonus (20%), gaze palsies (16%), and pupillary changes (48%) with waxing and waning character. Cerebellar signs were distinctly absent. Dystonia and decerebrate rigidity was observed in 43 and 6%, respectively, paralytic features in 17% and seizures in 30%. Many non-neurological features of prognostic importance included abnormal breathing patterns (ABP) (45%), pulmonary edema (PO) (33%), and upper gastrointestinal hemorrhage (UGIH) (16%). Injection dexamethasone was used in 1978 in all 208 cases, including 21 of PO. Patients were later randomized alternately in dexa and non-dexa groups. Forty-six cases of PO from the non-dexa group were transferred to the dexa group as an ultimate life-saving measure. Thus, it was administered in 737 of 1,199 patients including 529 patients from the later epidemics in doses of 4 mg IV every 8 h for 7 days. Of 1,199, 462 did not receive it. There was no significant difference in mortality (p > 0.05) between the dexa (42.47%) and the non-dexa group (42.86%). All PO cases expired; so after the exclusion of the PO cases from dexa group, the difference of 6.14% (42.86 and 36.72) became significant (p < 0.01) (511 of 1,199 (43%) expired, [320 of 511 (63%) died within 3 days of hospitalization]). Out of a total of 1,199 patients treated, 688 (57%) were discharged; 23 of 688 (3%) without any sequelae and 665 of 688 (97%) with neuropsychiatric deficits classified into nine groups. During the four epidemics, the diagnosis of JE was basically on identical clinical presentation of acute encephalitic syndrome (AES) consisting of (1) abrupt onset of fever, headache, and AS, (2) dystonias and various movement disorders, (3) opsoclonus and gaze palsies, (4) CSF findings, and (5) the presence of residual neuropsychiatric and neurological features in the survivors.