Harlequins retain the likes of Sam Smith, Robert Stegmann, Joe Marler and Luke Wallace - but the focus is very much on experimentation for the hosts.
Tom Williams returns from injury at full back, colossal prop James Johnston is handed a chance and Rory Clegg and Richard Bolt form a half-back partnership for the first time this season.
London Irish, meanwhile, make six changes to the side that beat Worcester in the Premiership last weekend.
David Paice and Chris Hala'ufia make way for James Buckland and Alex Gray respectively, while Paul Hodgson and Adrian Jarvis take over the half-back reins.
Irish head coach Toby Booth said: "The LV=Cup presents a great opportunity to continue the momentum we have gained in the Premiership. It is a tournament we will be taking seriously and want to do well in."
Harlequins: Williams, Stegmann, Urdapilleta, Casson, Smith, Clegg, Bolt; Marler, Brooker, Johnston, Twomey, Matthews, Wallace, Skinner, York.
Replacements: Buchanan, Lambert, Sinckler, Merrick, Trayfoot, Lindsay Hague, Hopper, Walker.
London Irish: Homer, Ojo, Spratt, Armitage, Thompstone, Jarvis, Hodgson; Lahiff, Buckland, Rautenbach, Kennedy (captain), Evans, Danaher, Gibson, Gray.
Replacements: Blaney, George, Ion, Sisi, Thorpe, Ansbro, Shingler, Samson.
Gilbert has released a new line of rugby cleats. The Gilbert Virtuo 8S is part of the exciting new product. Check it out.
The entire All Blacks apparel line has been updated for 2013/14. Check out the New Zealand All Blacks polo.
The Nike Tiempo is a solid rugby cleat and one of few styles still made from full-grain natural leather.
The Gilbert Blitz 8S rugby cleat is a great cleat at a great price of $69.99. Get a new pair of cleats today.
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Wear the crest of the British and Irish Lions on your t-shirt. A great look for the summer.
The All Blacks Performance t-shirt is black with hints of blue from the training jersey. Very Cool.
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The USA Rugby Pro Alternate rugby jersey is perfect for any fan of the Eagles. Get yours to wear during the summer Test matches.
The NEW All Blacks 2013/14 jersey has arrived at World Rugby Shop. Dare to wear the colors of the All Blacks.