Defending champion Spain welcomes the Americans after having won the last two series between them. Spain hasn't lost on clay, or at home, in 13 years. The Americans will play without Andy Roddick, who retired after the U.S. Open.
"Spain is the favorite. They could make three or four Davis Cup teams with how many players they have. (But) we'll take our chances,'' U.S. captain Jim Courier said Thursday. "The preparation is the same for us, no different. It's all about execution.''
John Isner stepped in to fill the void of Roddick's departure, with wins over Roger Federer, Jo-Wilfried Tsonga and Gilles Simon as he swept all four of his singles matchups in 2012.
Querrey will open Friday's singles against David Ferrer before Isner plays Nicolas Almagro. Isner and Sam Querrey are a combined 6-7 on clay.
"Our team has played in some tough environments before and we expect a tough environment tomorrow,'' said Isner, who earned his four wins against Switzerland and France. "It's going to be a big challenge, but it's not going to be anything I'm not used to.''
They'll play reverse singles on Sunday if neither team sweeps the best-of-five series. The winner will play the Czech Republic or Argentina in the final in November.
Ferrer and Almagro have a combined 21-1 record on the surface, making Nadal's injury absence a minor issue for captain Alex Corretja.
The fifth-ranked Ferrer, coming off a U.S. Open semifinal appearance, has had less time to recover but insists he'll be ready.
Ferrer will meet Querrey on clay for the first time after splitting their two previous matches on hard court. Querrey is playing Davis Cup for the first time in more than two years, with Mardy Fish and Ryan Harrison playing in previous series.
Spain has won three of the past four Davis Cups to become the dominant force in the competition, with victory over the U.S. in the 2004 and 2000 finals. The Americans have won the trophy a record 32 times.
Mike and Bob Bryan are overwhelming favorites to take Saturday's doubles after winning the U.S. Open title last week, their Open-era record 12th Grand Slam crown. The American twins have a 10-0 record on clay.
They'll play Spanish duo Marcel Granollers and Marc Lopez, who are 1-1 in their first season together. The pair made it through to the U.S. Open semifinals before Lopez retired in the first set because of a left calf injury.
"This could be our toughest away tie match,'' Mike Bryan said. "We'll treat it just like the U.S. Open final a week ago.''
The U.S. won on clay at Switzerland and at France to reach the semifinals. The hosts reached the final four without Nadal, who led Spain to its fifth title last year.
"He's the best clay-court player today, probably the best of all-time. If he was in the lineup, their lineup would be a little stronger,'' Isner said. "It's going to be tough either way, the team is so deep.''
Spain beat Kazakhstan and Austria to reach the semifinal at Parque Hermanos Castro in Gijon. The teams have split their previous 10 series, with Spain recently winning in Austin, Texas, and Madrid.