O'Brien and jockey Jim Culloty landed a 181-1 double with Illuminate and Equity's Double. But the stable's other runner at the meeting, Arctic Mist, fractured its pelvis in a fall and had to be put down.
After 6-1 chance Illuminate won the Heddon Novices' Handicap Hurdle, taking it up approaching the second-last flight to score by 11 lengths from Devonshire, a sad O'Brien said: "Arctic Mist is the first horse I have lost since starting training, and I hope he is the last. It has been a very up and down afternoon.
"I thought Illuminate had a chance with the favourite. The weight seemed to get to Devonshire as it is very sticky out there."
Equity's Double, 25-1, led on the run-in to take the closing Edenbridge Handicap Hurdle by five lengths from Fountain Bid.
The question of what big race Majadou will go for at the Cheltenham Festival was no nearer being answered after the French import's bloodless victory in the Adventure Novices' Chase, which completed a three-timer for Martin Pipe's gelding.
Majadou, who is entered in the Arkle, Cathcart and Royal & SunAlliance Chases at the meeting, made all and was never out of second gear to win by a distance from Bartholomew Fair, the only other finisher, Arctic Mist having fallen at the second-last.
Tony McCoy, who partnered the unbackable 1-14 shot, said: "He jumped left a bit, but he has always done that and Cheltenham and Aintree are left-handed so there are no worries there."