Case Description: A 64 year-old male presented with left-sided weakness and altered level of consciousness after a suspected seizure. MR Brain demonstrated right mesial temporal lobe diffusion restriction. Empiric antiviral and antibiotic treatments were initiated despite CSF negative for HSV/VZV and enteroviruses. Lumbar puncture on admission day five was unchanged and empiric treatments were discontinued. On day 13 he deteriorated into status epilepticus necessitating ICU transfer. A third lumbar puncture demonstrated elevated protein and HSV-1 positive PCR. Acyclovir was restarted with guarded prognosis. Discussion: Detection of HSV-1 in CSF is considered the diagnostic gold standard for HSV-1 encephalitis. The validated multiplex assay used in Alberta, Canada has a 95% level of detection significantly better than the recommended threshold for HSV laboratory diagnosis. Previous reports have indicated that CSF PCR may be negative early in the disease course. Others have suggested that initially negative/follow up positive HSV PCR cases may represent secondary reactivation or release from underlying tissue damage. Consideration of the full clinical picture is crucial in patients with HSV negative PCR. Continuation of antiviral therapy may be appropriate in select HSV PCR negative patients.