The Real Madrid defender hasn't featured for his national team, due to a thigh injury.
Portugal still decided to include Pepe in their squad call, however, he didn't feature in the 2-1 victory on Sunday against Serbia and ahead of taking on Cape Verde this coming Tuesday, the centre-back has been definitively ruled out.
As such, Pepe has been released from his international obligations and travels back to Madrid, where he'll undergo further evaluation, with the aim of recovering ahead of Real's encounter with struggling Granada, next Sunday in La Liga at the Santiago Bernabéu.
Meanwhile and ahead of the game against the Cape Verde selection, Portugal have seen their squad decimated through injuries and fitness doubts, with just 14 players amongst those expected to feature in Tuesday's encounter.
Those already ruled out include:
Rui Patrício, Bosingwa, Ricardo Carvalho, Bruno Alves, Eliseu, Tiago, Joao Moutinho, Nani, Fábio Coentrao, Cristiano Ronaldo, Danny, José Fonte, Ricardo Quaresma and William Carvalho.
The fourteen still available for Portugal are:
Marafona, André Almeida, André Pinto, Paulo Oliveira, Tiago Pinto, Pizzi, Danilo, André André, Adrien, Bernardo Silva, Ukra, Rui Fonte, Lucas Joao and Ivan Cavaleiro.
Funds from the match between Portugal and Cape Verde, taking place in Estoril, will go towards aiding those who suffered the impact of a volcanic eruption, which struck the African archipelago last November, forcing the displacement of hundreds of residents.