I'm the one who gripped you tight and raised you from Perdition.
– Castiel to Dean, 4.01 Lazarus Rising
When Dean is resurrected, he finds a handprint burnt into the skin of his left deltoid, presumably from when Castiel rescued him from Hell. When attempting to identify the being who raised Dean, psychic Pamela Barnes says she needs to touch something it touched, and Dean reveals the burn, and she places her hand over it.
The next time Dean is seen shirtless is when he dreams about making love to Lisa, when he is back hunting with soulless Sam. In his dream, Dean does not appear to still have the handprint on his shoulder. This is confirmed when Dean next disrobes when having sex with Lydia.
In 15.18 Despair, Castiel slices his hand and uses the Angel Banishing Sigil to keep Billie at bay. Once he experiences true happiness and summons the Cosmic Entity from the Empty, Castiel pushes Dean out of the way of the portal as the entity takes him and Billie, leaving a bloody handprint on his shoulder, over the place where the original handprint was burned onto his skin.
The Handprint in Fandom
The handprint features prominently in Dean/Castiel stories, and is held to be symbolic of Dean and Castiel's bond.
When it first appeared absent in 6.03 The Third Man, fans speculated that the scar had been removed when Castiel healed Dean of his wounds at the end of 5.22 Swan Song. This is also Jensen's theory.
Jensen has said that the scene in 15.18 Despair where Castiel pushes Dean out of the way and leaves his bloody handprint on his shoulder was improvised on the day and was either Misha's or Richard Speight Jr.'s (who was directing the episode) idea.