Only Atletico Madrid have matched Gerardo Martino's side so far, with Real Madrid two points back in third.
Barcelona have been in devastating form at the start of the campaign, scoring 18 goals in their opening five matches while only conceding four.
Cesc Fabregas will not feature for Martino's side after he was left out in order to have a rest, with Sergio Busquets coming in having missed the win over Rayo Vallecano.
Carles Puyol remains sidelined as he continues his rehabilitation from knee surgery.
Diego Simeone's side are unbeaten in their last seven meetings with Tuesday's opponents and they will hope that Diego Costa continues his rich vein of form to fire them to victory.
Carlo Ancelotti's side will be without world-record signing Gareth Bale (groin) but may have Iker Casillas and Sergio Ramos available after both men returned to training on Monday.
Madrid will be hoping to avoid a repeat of the last time they met a promoted side – they were were held to a 2-2 draw by Villarreal.
Marcelino Garcia Toral's side have made an excellent start on their return to the top flight and will look to continue that when they face Espanyol.
Like their opponents, Espanyol have started the season well, and have also yet to taste defeat this season.
Athletic won their first game in the new stadium against Celta Vigo but they have not beaten Betis in their last four attempts so will be wary of Pepe Mel's side.
Elsewhere, Levante welcome Real Valladolid to the Estadio Ciudad de Valencia on Tuesday, while Almeria travel to Malaga on Wednesday.
