Chelsea striker Alvaro Morata was left out after a
disappointing season in England, as was his teammate Marcos Alonso, with Arsenal's Nacho Monreal picked as back-up for left back Jordi Alba.
Lopetegui selected Atletico Madrid's Diego Costa, Celta Vigo's Iago Aspas and Valencia's Rodrigo Moreno as his three centre forwards, all relatively untested.
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Costa, who had a disappointing tournament in Brazil in 2014 as Spain were knocked out at the group stage, has scored seven goals in 18 internationals.
Versatile Barcelona midfielder Sergi Roberto was also omitted while veteran playmaker Andres Iniesta heads to his fourth World Cup along with captain Sergio Ramos.
Isco, Marco Asensio, Nacho Fernandez, Dani Carvajal and Lucas Vazquez are going to the tournament for the first time along with their Real Madrid teammate Ramos. Only four Barcelona players are in the Spain squad, down from seven Brazil four years ago.
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The 2010 world champions face Switzerland on June 3 and Tunisia on June 9 in friendlies before their World Cup campaign begins against Portugal on June 15.
Spain squad
Goalkeepers
David de Gea (Manchester United), Pepe Reina (Napoli), Kepa Arrizabalaga (Athletic Bilbao)
Defenders
Jordi Alba (Barcelona), Nacho Monreal (Arsenal), Alvaro Odriozola (Real Sociedad), Nacho Fernandez (Real Madrid), Dani Carvajal (Real Madrid), Gerard Pique (Barcelona), Sergio Ramos (Real Madrid), Cesar Azpilicueta (Chelsea)
Midfielders
Sergio Busquets (Barcelona), Isco (Real Madrid), Thiago Alcantara (Bayern Munich), David Silva (Manchester City), Andres Iniesta (Barcelona), Saul Niguez (Atletico Madrid), Koke (Atletico Madrid).
Forwards
Marco Asensio (Real Madrid), Iago Aspas (Celta Vigo), Diego Costa (Atletico Madrid), Rodrigo Moreno (Valencia), Lucas Vazquez (Real Madrid)
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