Switzerland have been dealt a double blow with the news that Alexander Frei and Valon Behrami will miss the game with Spain on Wednesday.
The pair have been ruled out of their side's World Cup opener in Durban after failing to recover from ankle and thigh injuries respectively.
Both players are expected to return to training on Thursday but the Swiss will have to do without them against the European champions.
Coach Ottmar Hitzfeld said: "They will not play on Wednesday.
"The aim is that they come back for the second match against Chile."
The experienced German tactician rejected suggestions that captain Frei, 30, could be out for the rest of the tournament.
"I'm really counting on him (Frei) for Monday (the next game)," Hitzfeld said regarding the striker.
Hitzfeld insists it is the same situation for 25-year-old Behrami, who plays for Premier League outfit West Ham.
"I didn't call on Valon Behrami so that he could carry on having treatment up to the Chile match," he added.
Switzerland have been drawn in Group H for the South Africa tournament and face Chile and Honduras as well as Spain.