This is a case of herpes simplex encephalitis (HSE) examined with 99mTc-ethyl cysteinate dimer (ECD) and 99mTc-hexamethyl propyleneamine oxime (HMPAO) SPECT. Static images obtained with 99mTc-ECD showed a reduced tracer uptake of the temporal lobe but focal hyperactivity using 99mTc-HMPAO. Dynamic images indicated regional increase of cerebral blood perfusion with both tracers. Technetium-99m-ECD had rapid washout from the inflamed tissue, while 99mTc-HMPAO had avid uptake. Hypofixation of 99mTc-ECD leads to failure to detect the characteristic finding of temporal lobe hyperemia in acute HSE.