The American claimed the title in 2013 by beating Branden Grace in a play-off at Castle Stuart.
That victory proved to be little more than a prelude to greater things for Mickelson, who went on to take the crown at The Open Championship a week later - the fifth major win of his career.
Mickelson will be aiming to repeat those heroics for the second straight year - but will need to be at his best if he is to retain the Scottish Open at Royal Aberdeen, which is playing host to the tournament for the first time.
A world-class field will be looking to dethrone Mickelson and head into the 143rd edition of The Open in good form.
No fewer than 23 players from inside the world's top 60 will be competing for the £3million prize fund, with another nine major champions hoping to prevent Mickelson from joining Bob Byman, Tom Watson and Tiger Woods as the only Americans to retain a title on the European Tour.
World number six Justin Rose and world number eight Rory McIlroy will perhaps be Mickelson's biggest challengers, although the pair go into the event having experienced contrasting recent fortunes.
Rose tasted his first success since the 2013 US Open with victory at the Quicken Loans National at Congressional nine days' ago, while McIlroy will be eager to bounce back after missing the cut at the Irish Open.
Another of Mickelson's rivals, Ernie Els, will be chasing history come the start of play on Thursday as the South African sets out to match the record of Ian Woosnam and win the trophy for a third time after doing so in 2000 and 2003.
The main Scottish challenge should come from world number 37 Stephen Gallacher, who has enjoyed a strong year with four of his five top 10 finishes coming on the European Tour.
English trio Lee Westwood, Luke Donald and Ian Poulter are likely to be in the running for the title, along with Race to Dubai leader Thomas Bjorn of Denmark.
Meanwhile, Americans Rickie Fowler, Ryan Palmer and Kevin Stadler will all be keen for strong showings on the links course ahead of The Open at Royal Liverpool.