The defender, who plays with his compatriot Ronaldo at Real Madrid, has suffered a calf strain, according to the club on its website, and will miss the final two matches of the season in La Liga, one in which Real Madrid are in the midst of a three-way title race.
The club estimated Pepe will be out for 15 days, putting his participation in doubt for the Champions League final on May 24, where Real Madrid will face city and league title rivals Atlético Madrid in Lisbon.
The blow comes on the heels of Cristiano Ronaldo's early exit from a league game on Wednesday due to an apparent injury. Though no official word has come from the club regarding his injury, ESPN's Dermot Corrigan reports the reigning Ballon d'Or winner is dealing with a problem hamstring and could also be an injury worry for the Champions League final.
In addition to the Champions League, Pepe and Cristiano Ronaldo are among the top players for Portugal at the World Cup this summer, where they will face the US national team in Group G, widely considered the tournament's Group of Death. The teams will clash in Manaus on June 22.