The deafening roars and piercing whistles of the Bilbao fans have often given their team extra impetus in the claustrophobic, 40,000-seater arena known as the Cathedral and the Basques are right in the tie after holding Barcelona to a 0-0 draw in last month's first leg at the Nou Camp.
"Bilbao are a team that will create problems for us," Barcelona coach Pep Guardiola said after the league leaders ground out a 2-1 home win over promoted Levante on Sunday.
Spain midfielder Iniesta has mostly been hailed as a hero by opposing fans for scoring the winning goal in July's World Cup final but that achievement cuts little ice with the fiercely independent Basques.
"Now we have a life or death match," Iniesta said after the Levante game.
Barca's arch-rivals Real Madrid have not won the domestic Cup since 1993 but virtually secured a quarter-final berth with an 8-0 demolition of Levante in the first leg.
Jose Mourinho's side, who play Levante on Thursday, look likely to go on and face city rivals and 2010 runners-up Atletico, who won their first leg at home to Espanyol 1-0.
Mourinho said Brazil playmaker Kaka, who had knee surgery after the World Cup and has not played this season, could get a run-out in Real's La Liga match at neighbours Getafe later on Monday.
"He won't start against Getafe and he is still nowhere near being able to," the Portuguese told a news conference. "He could give us 15 or 20 minutes of his super quality but no more."
