Cristiano Ronaldo and Pepe during training session at Al Shahaniya Stadium, Qatar, on Monday. Reuters
Nuno Mendes gets the nod over Raphael Guerreiro at left-back for Portugal and William Carvalho comes into midfield in place of Otavio.
Edinson Cavani was picked ahead of fellow Uruguay icon Luis Suarez in attack as coach Diego Alonso switches his formation from a back four to a back three.
Centre-back Sebastian Coates comes in with winger Facundo Pellistri dropping to the bench while Guillermo Varela is picked at right wing-back instead of veteran Martin Caceres.
Starting line-ups in the World Cup Group H match between Portugal and Uruguay at Doha's Lusail Stadium on Monday (kick-off 1900 GMT):
Portugal (4-2-3-1)
Diogo Costa; Joao Cancelo, Ruben Dias, Pepe, Nuno Mendes; William Carvalho, Ruben Neves; Bruno Fernandes, Bernardo Silva, Joao Felix; Cristiano Ronaldo (capt)
Coach: Fernando Santos (POR)
Uruguay (3-5-2)
Sergio Rochet; Jose Maria Gimenez, Diego Godin (capt), Sebastian Coates; Guillermo Varela, Federico Valverde, Rodrigo Bentancur, Matias Vecino Mathias Olivera; Edinson Cavani, Darwin Nunez
Coach: Diego Alonso (URU)
Referee: Alireza Faghani (IRI)
Agence France-Presse