The song features American singer-songwriter and "Godmother of Punk" Patti Smith performing backing vocals. Smith was cited as a major influence by band members Michael Stipe and Peter Buck and also provided backing vocals for "Blue" the closing track on the band's final studio album Collapse into Now.
The song's title refers to the EBow, an electromagnetic field-generating device that induces sustained vibration in an electric guitar string (creating a violin-like effect), and to a "letter never sent" by Michael Stipe. Guitarist Peter Buck can be seen using an EBow in the video for the song at approximately 1:27 to 1:30. R.E.M. has also played the song live with artists including Thom Yorke singing Patti Smith's vocal part. During the music video, Michael Stipe can be seen scribbling something on a music sheet, revealing that Stipe is left-handed. The song is about Stipe's great friend, the actor and musician River Phoenix.
"E-Bow the Letter" was ranked number 21 on NME magazine's list of the "Singles of the Year". In 2003, the song was placed on R.E.M.'s compilation In Time: The Best of R.E.M. 1988-2003. Pitchfork Media founder and owner Ryan Schreiber described it on the website as "possibly one of the greatest songs ever written."