We performed a long-term magnetic resonance imaging (MRI) study in a mouse model of herpes simplex virus encephalitis. Mice were infected with herpes simplex virus type 1 (HSV-1) strain F. A 1.5-T cranial MRI scanner with standard spin-echo sequences was used. Neuropathological studies included immunohistochemistry. The presence of HSV DNA in brain tissue was determined with a polymerase chain reaction assay. Clinical assessment was performed daily: within the first 2 weeks the animals were severely affected and recovered thereafter. MRI and histopathological abnormalities corresponded well. HSV DNA was detectable initially and at 6 months. Extent and severity of structural abnormalities increased at 6 months. MRI offers a new in vivo approach for the detection of structural changes in the disease course of experimental herpes simplex virus encephalitis.