OBJECTIVES: High index of suspicion is mandatory for early diagnosis of Herpes Simplex Encephalitis (HSE), since acyclovir therapy can prevent its mortality and limit morbidity. We report our observations on clinical spectrum, pitfalls in diagnosis and therapeutic aspects in patients of HSE. METHODS: There were 34 patients of HSE (26 males and eight females) in age range 6 -72 (mean 23.8 +/- 8.9) years. Diagnosis was confirmed by cranial MRI, EEG and PCR in CSF. Acyclovir was given to 24 patients. Carbamazepine and sodium valproate were the antiepileptic drugs used. RESULTS: Most of the patients were referred either as Japanese encephalitis, cerebral malaria or tubercular meningitis. High fever, seizures, behavioral abnormality and encephalopathy were present in all, either at onset or later. EEG, CSF abnormality and cranial MRI were abnormal in all 34 patients. PCR for Herpes Simplex virus was positive in 65 % cases CT was performed in 10 cases but abnormality was detected only in four. We observed features of Kluver Bucy syndrome in three patients, suffering from HSE. Following complete acyclovir therapy in 24 patients, 12 recovered completely and four partially. There was no improvement in four patients including two patients who had features of Kluver Bucy Syndrome, while four expired. Among the seven patients who refused therapy of acyclovir, five expired, while two remained in unaltered status. Treatment could not be completed in three patients as they expired during therapy. CONCLUSION: HSE is commonly misdiagnosed. Important factors influencing mortality and morbidity of HSE were; early acyclovir therapy, age, immune status of patient, duration of illness, and consciousness level before initiation of therapy. We conclude that acyclovir should be given to all patients as soon as suspected, while confirmatory investigations are in progress.