This is the sheet that surrounds the nerve. It is a dense connective tissue, the surface of which is nourished by a thin vascular plexus (only limited lymph vessels) known as the vasa nervorum. Normal peripheral nerves freely glide in the adjacent soft tissues during movement; this plane is a potential space for disease infiltration.

The epineurium represents a continuum with the pia-arachnoid from the central nervous system and extends distally with the sheath of capsular cells of peripheral sensorial organs and propioceptive receptors. Functionally, the perineurium modulates external stretching forces (that could be potentially harmful for nerve fibers), and along with endoneurial vessels, forms the blood-nerve barrier. The perineurium is the last connective tissue layer to break when a nerve is subjected to extreme traction.