Barcelona, Manchester City and Arsenal could all lose South American star players such as Lionel Messi, Sergio Aguero and Alexis Sanchez for a game in November because of the intercontinental World Cup playoff.
One of Uruguay, Colombia, Peru, Argentina, Chile, Paraguay and Ecuador will finish fifth in the CONMEBOL qualifying table, forcing them to play a two-legged tie against New Zealand for a place at the World Cup in Russia.
The first leg of the playoff has been set for the week of Monday, Nov. 6, in Wellington, and the second leg will take place the following week in South America, on Tuesday, Nov. 14.
FIFA rules say clubs must release their players four days before a World Cup qualifier, so anyone selected for that fixture may not be able to play for their club over the weekend.
Barcelona face a tough fixture at home to Sevilla, and could lose Lionel Messi and Javier Mascherano should Argentina end up in the playoff. Luis Suarez is a doubt too, but Uruguay are highly likely to qualify automatically. But if Barca lose Messi, then Sevilla could be without up to five Argentina players that they had in the most recent squad.
There are some big fixtures in the Premier League too, with Manchester City hosting Arsenal -- so Pep Guardiola could lose Nicolas Otamendi and Sergio Aguero, or the Gunners could be without Alexis Sanchez.
Manchester United travel to Chelsea, and with Ecuador still fighting to qualify that puts Antonio Valencia's availability in doubt.
Argentina dropping into the playoff would have by far the biggest effect on Europe's biggest clubs, with potentially 18 players ruled out.
New Zealand's qualification will affect a couple of Premier League clubs, with Winston Reid set to miss the home game with Liverpool and Chris Wood likely out of Burnley's trip to Southampton.
Players at major European clubs who could be affected. Only one of these nations will take on New Zealand.
Uruguay: Joss Maria Gimenez, Diego Godin (both Atletico Madrid), Matias Vecino (Inter Milan), Luis Suarez (Barcelona), Edinson Cavani (Paris Saint-Germain)
Colombia: David Ospina (Arsenal), Cristian Zapata (AC Milan), Davinson Sanchez (Tottenham), Juan Cuadrado (Juventus), James Rodriguez (Bayern Munich), Jose Izquierdo (Brighton), Radamel Falcao (Monaco), Luis Muriel (Sevilla)
Peru: Andre Carrillo (Watford)
Argentina: Sergio Romero (Man United), Nicolas Pareja, Gabriel Mercado, Guido Pizarro, Ever Banega, Joaquin Correa (all Sevilla), Federico Fazio (Roma), Javier Mascherano, Lionel Messi (both Barcelona), Nicolas Otamendi, Sergio Aguero (both Man City), Lucas Biglia (AC Milan), Augusto Fernandez (Atletico Madrid), Angel Di Maria, Javier Pastore (both Paris Saint-Germain), Paulo Dybala, Gonzalo Higuain (both Juventus), Mauro Icardi (Inter Milan)
Chile: Claudio Bravo (Man City), Arturo Vidal (Bayern Munich), Alexis Sanchez (Arsenal)
Paraguay: Gustavo Gomez (AC Milan)
Ecuador: Antonio Valencia (Man United), Felipe Caicedo (Lazio)