"St. James Infirmary Blues" (also "St. James Infirmary" or "Saint James Infirmary") is based on an 18th century traditional English folk song of anonymous origin, though sometimes credited to the songwriter Joe Primrose (a pseudonym for Irving Mills). Louis Armstrong made it famous in his influential 1928 recording.

"St. James Infirmary Blues" is based on an 18th century traditional English folk song called "The Unfortunate Rake" (also known as "The Unfortunate Lad" or "The Young Man Cut Down in His Prime"). There are numerous versions of the song throughout the English-speaking world. It also evolved into other American standards such as "The Streets of Laredo". "The Unfortunate Rake" is about a sailor who uses his money on prostitutes, and then dies of a venereal disease. Different versions of the song expand on this theme: variations typically feature a narrator telling the story of a youth "cut down in his prime" (occasionally "her prime") as a result of some morally questionable actions. For example, when the song moved to America, gambling and alcohol became common causes of the youth’s death.

The title is derived from St. James Hospital in London, a religious foundation for the treatment of leprosy. It was closed in 1532 when Henry VIII acquired the land to build St. James Palace.

The song was first collected in England in its version as "The Unfortunate Rake" by Henry Hammond by a Mr. William Cutis at Lyme Regis, Dorset in March 1906.

The song involves a man telling the singer/narrator, at a bar, how he went down to St. James Infirmary (hospital) and tragically found his girl (the so-called "baby") dead.

Like most such folksongs, there is much variation in the lyrics from one version to another. As a representative version, here is the first stanza as sung by Louis Armstrong:

I went down to St. James Infirmary,
Saw my baby there,
Stretched out on a long white table,
So cold, so sweet, so fair.
Let her go, let her go, God bless her,
Wherever she may be,
She can look this wide world over,
But she'll never find a sweet man like me.

Notable performers of this song include Abner Jay, Cab Calloway, James Booker, Duke Ellington, Louis Armstrong, Kermit Ruffins, King Oliver, Artie Shaw, Big Mama Thornton, Jack Teagarden, Wingy Manone, Billie Holiday, Cassandra Wilson, Stan Kenton, Lou Rawls, Bobby Bland, Ramblin' Jack Elliott, Doc Watson, Dave Van Ronk, "Spider" John Koerner, Janis Joplin, The Doors, Paul Butterfield, The Animals, The Standells, and more recently The White Stripes, The Devil Makes Three, the Stray Cats, the Tarbox Ramblers, Snooks Eaglin, Hugh Laurie, Isobel Campbell and Mark Lanegan, and Tom Jones with Jools Holland. Jazz guitarists Marc Ribot and Ivan "Boogaloo Joe" Jones have recorded instrumental versions. The person holding the copyright is listed as Joe Primrose. According to the song's publisher (EMI), Irving Mills, using the pseudonym Joe Primrose, took the copyright on the song in 1929. However, the Louis Armstrong recording was actually made in late 1928. One of the only recordings, if not the "only" recording, that pre-dates Armstrong's is a performance by Fess Williams and his Royal Flush Orchestra, made February 25, 1927 in New York City. The song is listed as "Gambler's Blues," and the writer credit is "Moore-Baxter." In spite of having a different name, the lyrics and tune are close enough to be considered the same song.

Van Morrison recorded a rendition on the 2003 Grammy-nominated album, What's Wrong with This Picture? and a live version on the limited edition album, Live at Austin City Limits Festival (2006). Eric Clapton and Dr. John performed a rendition of the song during a 1996 concert. Arlo Guthrie performed a rendition on NPR's Talk of the Nation on November 14, 2001. The Preservation Hall Jazz Band performed it at the 2010 Newport Folk Festival (recorded by NPR). Robert Crumb released a version on a CD included in the R. Crumb Handbook. Live versions appear on Joe Cocker's albums Joe Cocker (1972), and Live in L.A. (1976).

The Bing Crosby musical Birth of the Blues featured the song in 1941. Cab Calloway can be seen singing it and dancing a slide dance in the Betty Boop cartoon Snow White. His performance was filmed, then transferred into the cartoon using rotoscoping. In 2002, the song appeared in Osamu Tezuka's anime film Metropolis as performed by Atsushi Kimura and arranged by Toshiyuki Honda.

In November, 1975, Lily Tomlin performed "St. James Infirmary" with Howard Shore and His All-Nurse Band on "NBC's Saturday Night" (later to be known as Saturday Night Live), which was the SNL band dressed up in nurse uniforms. Paul Shaffer was the piano player in the performance.

The Mystic Knights of the Oingo Boingo performed this song regularly on their tours of the US in the early 1970s.