US Middle East envoy George Mitchell is resigning after two years in the role.
The former senator and broker of the peace deal in Northern Ireland has shuttled between the Israelis and Palestinians trying to bring the two sides together for peace talks.
His resignation is effective from 20 May. Deputy Middle East envoy David Hale will serve as acting envoy.
The BBC reports Mr Mitchell, 77, was appointed by President Barack Obama in early 2009.
His efforts culminated in September in a short round of direct talks between Israeli Prime Minister Benjamin Netanyahu and Palestinian President Mahmoud Abbas.
But the negotiations fell apart after Israel declined to extend a moratorium on construction of settlements in the occupied West Bank.
Mr Obama praised Mr Mitchell's ''deep commitment to resolving conflict and advancing democracy''.
He is due to make a speech next week on US policy in the Middle East.
Mr Mitchell was nominated for the Nobel Peace Prize for helping President Bill Clinton broker the 1998 Good Friday peace accords in Northern Ireland.