The closest the Ballydoyle trainer came to landing one of the most sought-after races in world racing was when Giant’s Causeway painfully lost out to Tiznow by a neck in 2000.
But in Declaration Of War, O’Brien arguably has one of his strongest contenders for quite some time.
The four-year-old colt has long been considered an ideal type for the Santa Anita dirt and will go to post in America a fresh horse at the top of his game.
Declaration Of War demonstrated his aptitude for this mile-and-a-quarter trip on his last outing at York in August, when he charged clear in the Juddmonte International Stakes.
Now comes his sternest test to date.
O’Brien said: “I don’t even dream or think about it (winning the Classic), because there are so many things to consider.
“You have to keep doing your best and try to make the right decisions. This is so far from being an exact science and all I know is that his condition is very good going into this race.
“He’s a big, strong traveller and a powerful horse who loves fast ground. There’s plenty of dirt in his pedigree.
“We’ve tried to replicate things he could encounter. He’s worked out of American stalls and he was in Southwell a couple of weeks ago.
“In our part of the world, Southwell is as close to the dirt as we can get. All that seemed to go well.
“We’ve done our best and we’ll see if that’s good enough when he runs.”
British interest is spiked by the presence of Planteur, trained in Newmarket by Marco Botti.
Ryan Moore’s partner, who will wear a first-time hood, is a seasoned traveller, but must atone for a disappointing run in the Prix Dollar on Arc weekend.
Lucie Botti, wife of the Italian-born trainer, said: “I am very happy with Planteur.
“He has done well out here, the work is all done, and we are hoping for the best.”
Fort Larned has been rather in and out since he won the Classic last year, but geared up for this with a no-nonsense success at Churchill Downs in September.
Trainer Ian Wilkes said: “He stumbled (unseated rider) earlier in the year and that really put us off course. After that I tried to make it up and it was probably a bad decision.
“I feel like the horse is back to his old self. He travels well and has always been a good shipper.
“My horse is ready.”
Game On Dude was meekly turned over as the short-priced favourite last season, but has since won six races on the spin – three of which were in Grade One company.
He also finished second to Drosselmeyer in the Classic two years ago.
Trainer Bob Baffert said: “He’s the only horse I’ve ever had that’s made over 5million and never been a champion.
“We feel like he couldn’t be training any better. He looks great.
“Last year did go awry. But I think he’s a different horse than he was last year.
“He’s really run some outstanding races, and he doesn’t show me any signs of tailing off.”
Baffert also runs Paynter, who was runner up to last year’s runner-up Mucho Macho Man, trained by Kathy Ritvo, in a Grade One here in September.
Ritvo said: “He’s prepared and I’m blessed. We are 100% focussed on Mucho Macho Man.
“I just want everything for him. He deserves it.”
Will Take Charge is another ominous challenger from the home team after the three-year-old colt won his last two races in some style.
Trainer D Wayne Lukas said: “Maturity is the big thing with him.
“He’s 17 hands tall and he will probably be a better four-year-old, if you want to know the truth.
“One of the things that’s significant is that he started running in January and he’s run in every three-year-old race in the country.
“Nobody else has.”