The treble winners were shown to be vulnerable after breaks for internationals last season, and with lingering doubts over the strength in depth of their squad this time round, a visit to giant-killing specialists Getafe is a tough assignment.
"Iniesta's return is very important for the team as he is a unique player of outstanding quality. He can decide a game on his own," Barca defender Maxwell told a news conference.
"It's difficult to work when there are so many players away and it is possible that Getafe have the advantage. But we aren't looking for excuses."
Madrid-based Getafe flirted with relegation last year but under former Spain and Real Madrid midfielder Michel, they have undergone a rapid transformation.
Since losing his opening game at the helm last April, they are unbeaten in 15 consecutive matches between the end of last season, pre-season friendlies, and their opening day thrashing of Racing Santander 4-1.
Real Madrid proved they were a work in progress in their laboured 3-2 home victory over Deportivo Coruna, and will be seeking an improvement away to Espanyol on Saturday.
NEW STADIUM
It will be a momentous day for the Barcelona-based hosts who will be playing their first competitive match in their new stadium Cornella-El Prat.
It will be an emotional one as well, as they play their first league game in front of their own fans since the sudden death of defender Dani Jarque from a heart failure last month.
"It's a big game for us, it fills us with motivation, and we are going to give our all for it to be a great encounter," Espanyol coach Mauricio Pochettino said.
Real have Spain full back Sergio Ramos back in contention after three months out with tendinitis.
One match in and Atletico Madrid's board are already on the defensive ahead of Saturday's visit of Racing Santander.
Their 3-0 defeat at Malaga quickly wiped away the joy at having qualified for the group stages of the Champions League last month.
Fans unhappy with the side's failure to make any significant moves in the transfer market, particularly after having achieved their place in Europe's elite competition, are planning protest demonstrations at the Calderon.
"Before they criticised us for signing too many players, now they say we don't sign enough. I don't understand it," president Enrique Cerezo told Spanish state radio.
