Since treatment of herpes simplex virus encephalitis (HSVE) is most effective when started early, a sensitive and specific method for early diagnosis would be of great benefit. MRI and CT are commonly used for this purpose. In this study, we presented two patients who had serologically confirmed HSVE and had normal CT and MRI, but were diagnosed as having HSVE by means of SPECT in the early stage. Case 1 was a 56-year-old man who suddenly developed alexia. On admission, physical and neurological examination were unremarkable except for alexia, agraphia, acalculia, and left-right disorientation. Brain CT, MRI, and cerebral angiography were all normal. However, SPECT showed hyperaccumulation of 99m Tc-HM-PAO in the right temporal-occipital area. On the 5th hospital day, he became comatose. CSF study revealed marked pleocytosis. Even then, MRI including Gd-enhanced study was normal while SPECT continued to show hyperaccumulation. Detection of herpes simplex virus DNA in CSF by polymerase chain reaction was negative. Anti-HSV antibody titer in CSF and serum confirmed intrathecal production of the antibody on the 14th hospital day. Abnormal accumulation of tracer in SPECT returned to normal on the 31st day when he was alert but still had a mild Gerstman syndrome. Case 2 was a 61-year-old man with disturbance of consciousness, mental dysfunction, and generalized convulsion. He was diagnosed as having HSVE by means of CSF pleocytosis, detection of HSV DNA in CSF by polymerase chain reaction, and presence of anti-HSV antibody in the CSF. CT and MRI again revealed no abnormality while SPECT clearly showed hyperaccumulation in the left temporal lobe in an early stage. Hyperaccumulation of lipophilic tracer on SPECT study, especially in the temporal lobes, has been reported in the early stage of HSVE by previous investigators. Unlike MRI or enhanced CT, the increased tracer accumulation in SPECT does not reflect disruption of the blood-brain-barrier or inflammatory edema, but reflects hyperperfusion or some other HSVE related abnormality which is currently unknown. From these observations, we suggest that local hyperperfusion occurs before local inflammation, and that SPECT is the most useful scanning method for early diagnosis of HSVE when this disease is clinically suspected.