Gianluigi Buffon and Mauro Camoranesi have been ruled out of Italy's World Cup qualifiers against Bulgaria and Montenegro.
Italy, who lead World Cup qualifying Group 8 with six points from two games, travel to Bulgaria on Saturday before facing Montenegro at home next Wednesday.
However, goalkeeper Buffon has sustained a muscle tear in his right leg and is set to be sidelined for around a month.
Midfielder Camoranesi also has a right leg injury which team doctor Enrico Castellacci expects to keep him out for at least two weeks.
Siena keeper Gianluca Curci will replace Buffon in the squad, while Palermo's Marco Amelia is likely to take his place in the starting line-up.
Lyon defender Fabio Grosso and Juve pair Nicola Legrottaglie and Vincenzo Iaquinta will also miss the games due to injury and Marcello Lippi called up four uncapped players - Giuseppe Rossi, Simone Pepe, Christian Maggio and Fabiano Santacroce - on Sunday.
"It is a period in which we have lots of injuries. It happens," Lippi said.
Veteran Juventus striker Alessandro Del Piero has been overlooked by Lippi despite all the injury problems.
However, Lippi has assured the 33-year-old that his international career is not over.
"I called him, we talked," Lippi explained to reporters.
"I wanted to look at some new players, I explained this to him and he understood. I also told him to continue doing what he has always done."