A 31-year-old woman with systemic lupus erythematosus (SLE) developed meningoencephalitis, followed by transverse myelitis. The clinical picture was otherwise not consistent with a lupus flare. Extensive diagnostic evaluation was unrevealing. Acute visual loss ensued, associated with an unusual pattern of retinitis. Endoretinal biopsy established the diagnosis of herpesvirus infection. Reinstitution of antiviral therapy, and optic nerve sheath decompression, led to resolution of neurologic deficits and partial return of vision. Our report is the first that describes a patient with SLE with herpes meningoencephalitis, transverse myelitis, and rapidly progressive outer retinal necrosis, diagnosed antemortem by endoretinal biopsy, and successfully treated with acyclovir and optic nerve fenestration.