Everton boss Roberto Martinez says an ankle injury to left-back Leighton Baines is a "disaster".
Baines, 30, missed the final two Premier League games of last season after having surgery on the same ankle.
"We don't know how long he will be out for, but it has been a real disaster," said Martinez.
"We were preparing for the Watford game and in training, he blocks the ball and it hits him in exactly the same place where he had surgery."
Everton drew 2-2 with the Hornets on the opening day and will have to manage without Baines for the foreseeable future.
The England international also seems set to miss his country's European Championship qualifiers against San Marino and Switzerland on 5 and 8 September.
"It was devastating, because he had worked so hard and looked stronger than ever," added Martinez, who replaced Baines with Brendan Galloway against Watford.
"I don't think I had seen him looking as powerful and refreshed in the last two seasons. Then there was this big knock.
"We still have to find out how long it will be, but it is not going to be just two or three weeks - I think it is going to be a little bit longer than that."
Asked if Baines would need another operation, Martinez added: "We don't know, but it could be.
"The surgery was to reinforce that ligament in his ankle and we still need to see the real extent of the damage. After the inflammation, we will find out."