Grayson in for world cup Wilko for Italian opener
But while the selection of Northampton fly-half eflects a clear safety-first strategy, Woodward's adventurous streak has also reappeared.
Jason Robinson, England's World Cup final try-scorer, will start a Test match for the first time at centre.
Robinson, Iain Balshaw, Josh Lewsey and Ben Cohen 63 England tries between them all make for a line-up bristling with pace and attacking invention.
Their combined presence especially with Robinson, normally a wing or full-back, operating directly alongside gifted England playmaker Will Greenwood in midfield promises a busy afternoon for the Italian defence at Stadio Flaminio.
Gloucester wing James Simpson-Daniel would also have been in the mix but he was not considered due to injury.
Simpson-Daniel's run of bad luck shows no sign of ending. After suffering glandular fever last season, and then narrowly missing out on World Cup selection several months later, he now has a rib problem.
"I am very excited about the team," said Woodward, who will parade 10 of his World Cup final side as England begin their Six Nations title defence.
"The starting fifteen are all guys that have been involved with the World Cup, and I expect them to move very swiftly into gear.
"It was interesting selecting the side, and there are new players coming into a World Cup-winning team.
"Some changes were made due to injury, and some through retirement, but I'm very excited about the team and looking forward to working with Lawrence Dallaglio as captain."
Grayson, aged 32, takes over from Wilkinson, who will undergo shoulder surgery on Wednesday and then a recovery period of six to eight weeks.
Although the experienced Grayson made his England debut more than eight years ago, he has never started a Six Nations game.
But with 357 Test points in the bank only Wilkinson and Rob Andrew have scored more for England he was an obvious choice, despite the claims of Bath's Olly Barkley and Wasps fly-half Alex King.
"Paul is the best player," added Woodward. "And I am very mindful we've had no training time at all since the World Cup, so to throw in Olly Barkley or Alex King with hardly any preparation would be a big call, especially playing away from home."
Elsewhere, Gloucester scrum-half Andy Gomarsall has won the vote over Matt Dawson, whose post-World Cup game time has been severely restricted by shoulder and calf muscle injuries.
Bath captain Danny Grewcock replaces legendary England leader Martin Johnson.
World Cup skipper Johnson's retirement from the Test arena leaves a major void, but 43 times capped Grewcock has a similar hard edge and no-nonsense approach required at international rugby's coalface.
Wasps lock Simon Shaw, who replaced an injured Grewcock during the World Cup campaign, is surprisingly overlooked for a place in England's 22. Steve Borthwick, Grewcock's Bath colleague, will provide second-row bench cover.
Also featuring among the replacements are Sale Sharks forward Chris Jones, Gloucester's former rugby league star Henry Paul and Bath goalkicker Barkley.
Jones is the only uncapped player in Woodward's first Test match since the World Cup triumph. The 6ft 6in 23-year-old, who can play second-row or back-row, has a big future ahead of him.
Paul's solitary England cap came against France in Paris almost two years ago, but consistently impressive club form this term meant an inevitable recall. He can count himself unlucky to not be starting.
As expected, Wasps flanker Joe Worsley takes over from axed World Cup star Neil Back, with Richard Hill switched from blindside to openside flanker.
Greenwood will replace Wilkinson as vice-captain, with Woodward stating: "He's a tremendous leader behind the scenes, and has always helped out Jonny in that role.
"So now with Jonny not being available, it is important Will steps into the frame, especially in our attacking play."
England will train at their Surrey base until Thursday, when they leave for Rome and a third visit to the Stadio Flaminio.
The two previous occasions, in 2000 and 2002, realised victories of 59-12 and 45-9.
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