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England international Hargreaves has been out for nearly 18 months following major surgery on both knees.
Meanwhile O’Shea has not played a game since suffering complications in his recovery from a dead leg sustained in the Republic of Ireland’s World Cup play-off defeat to France in November.
Wayne Rooney (ankle) is out, so Dimitar Berbatov is set to lead United’s forward line.
Striker Didier Drogba has recovered from a leg injury and spearheads Chelsea’s attack. Michael Essien (knee), Ashley Cole (ankle), Ricardo Carvalho (ankle), Jose Bosingwa (knee) and Branislav Ivanovic (knee) remain sidelined.
Last season: Man United 3 Chelsea 0, Chelsea 1 Man Utd 1
Last five league matches: Man United W W W W W; Chelsea L W D W W
Top scorers (all competitions): Wayne Rooney (Man United) 34; Didier Drogba (Chelsea) 30