Sir Des Champs, runner-up to Bobs Worth in the 2013 Cheltenham Gold Cup, is out for the season with a leg injury.
The horse, trained in Ireland by Willie Mullins, was around 6-1 third favourite for this year's big race in March.
"He has suffered slight damage to a tendon," said Mullins.
Sir Des Champs is owned by Gigginstown House Stud, which has confirmed 21-year-old Bryan Cooper as its new retained rider,replacing Irish champion jockey Davy Russell.
"The injury is going to take time to heal so we have decided to pull the plug on the remainder of the season," added Mullins.
Sir Des Champs won the Martin Pipe Handicap Hurdle and Jewson Novices' Chase at consecutive Cheltenham Festivals before finishing second in March under AP McCoy.
The 18-time champion jockey was a late call-up for the ride after Russell suffered a punctured lung in a fall.
Russell was back on board when Sir Des Champs defeated Long Run and fellow Gigginstown chaser First Lieutenant in the Punchestown Gold Cup. the following month.
The eight-year-old Sir Des Champs fell on his seasonal return and was fourth behind Bobs Worth in the Lexus Chase at Leopardstown on 28 December.
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