Many autoimmune diseases can affect the central nervous system, and their varying clinical presentations often confound a straightforward diagnosis. In this report, we describe a unique presentation of CLIPPERS syndrome. To our knowledge, this is the first case to demonstrate significant supratentorial involvement with symmetric and non-confluent lesions in the medial orbitofrontal cortex; additionally, this is the second case to describe an association between diagnoses of hypothyroidism and CLIPPERS.