Altior has been ruled out of the Betway Queen Mother Champion Chase at the 11th hour for a second successive year.
Nicky Henderson's 11-year-old, who has won the race twice previously as well as the Arkle and the Supreme Novices' Hurdle, coughed after exercise today.
The veteran has only made it to the track twice since November 2019 when he met with his first defeat over obstacles at the hands of Cyrname.
Altior was forced to miss last year's Queen Mother with a splint which emerged the weekend beforehand.
Henderson released the news via a statement on Twitter which read: "We are very sorry that we have taken the decision not to run Altior in the Champion Chase on Wednesday.
"He coughed after exercise this morning, which caused us to scope him, and as a result of what we have seen it would not be sensible to run him."
Meanwhile Annie Mc has been ruled out of the Mrs Paddy Power Mares' Chase.
The Jonjo O'Neill-trained seven-year-old, owned by Coral Champions Club, has suffered a minor setback which is enough to force her to miss Friday's Grade Two contest over an extended two and a half miles.
"Unfortunately Annie Mc has had a setback and will miss the Festival," said Simon Clare, Ladbrokes Coral PR director.
"Fortunately it's not a serious issue, and she could still run again this season. Cheltenham has just come a week too soon.
"We are naturally disappointed, but she's been an absolute star for us, and there will be more big days ahead for her."
Annie Mc was as low as 7-1 for what is a new race at the Festival, having won her last two starts well at Doncaster and Warwick.