With international commitments taking their toll, Saints head coach Jim Mallinder has handed a debut to Tom Stephenson in the centres.
There are a further five players who could make their first appearances off the bench; props Ethan Waller and Danny Herriott, scrum-half Alex Day and backs Anders Mogensen and Tom Collins are all amongst the replacements.
Ryan Lamb starts at fly-half and Luther Burrell returns to partner Stephenson in the centres in a team that is captained by flanker Calum Clark.
Quins are without several regulars themselves, with five of their players picked in the England squad to face Fiji at Twickenham this weekend.
Rory Clegg and Charlie Walker have also been ruled out through injury this week, joining Will Skinner, George Merrick and Ross Chisholm on the sidelines.
Ben Botica starts at fly-half, alongside Karl Dickson, for the tough trip to Franklin's Gardens.
Pete Browne and Joe Trayfoot make their first start of the season, while open-side flanker Luke Wallace captains the side for the first time.
Jack Clifford, Jordan Burns, Louis Grimoldby and Miles Mantella will make their first senior appearances for the club if they are used from the bench.
Northampton: 15 Tom May, 14 Scott Armstrong, 13 Tom Stephenson, 12 Luther Burrell, 11 Jamie Elliott, 10 Ryan Lamb, 9 Martin Roberts, 8 GJ Van Velze, 7 Ben Nutley, 6 Calum Clarke (c), 5 Rhys Oakley, 4 Mark Sorenson, 3 Paul Doran Jones, 2 Mike Haywood, 1 Alex Waller.
Replacements: 16 Ross McMillan, 17 Ethan Waller, 18 Danny Herriott, 19 Christian Day, 20 Teimana Harrison, 21 Alex Day, 22 Anders Mogenson, 23 Tom Collins.
Harlequins: 15 Ollie Lindsay-Hague, 14 Seb Stegmann, 13 Matt Hopper, 12 Harry Sloan, 11 Sam Smith, 10 Ben Botica, 9 Karl Dickson, 8 Tom Guest, 7 Luke Wallace (c), 6 Joe Trayfoot, 5 Charlie Matthews, 4 Pete Browne, 3 Will Collier, 2 Dave Ward, 1 Mark Lambert.
Replacements: 16 Rob Buchanan, 17 Darryl Marfo, 18 Kyle Sinckler, 19 Sam Twomey, 20 Jack Clifford, 21 Jordan Burns, 22 Louis Grimoldby, 23 Miles Mantella.
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