Defending champions River Plate suffered a surprise 2-0 defeat at Independiente del Valle in the first leg of their Copa Libertadores last-16 tie.
After a goalless opening half in Sangolqui in Ecuador on Thursday, Jose Angulo's 64th-minute opener and Junior Sornoza's stoppage-time penalty sealed the home win for Independiente.
River had only lost one match in the group stages, and that was away from home earlier this month.
And their poor away form - just one win in seven games in all competitions - came back to haunt the Argentine giants again.
Angulo made the breakthrough for Independiente just past the hour-mark, when he fired the ball past Marcelo Barovero, after receiving a pass from Bryan Cabezas inside the penalty box.
Ecuador international Sornoza made sure of the win in the second minute of additional time in the second half, converting a spot-kick.
River's result left Boca Juniors to fly the Argentina flag on Thursday, and they did via a 2-1 victory away to Cerro Porteno.
Former Juventus and Manchester City forward Carlos Tevez set Boca on their way in Paraguay, giving the visitors a 29th-minute lead at Estadio Defensores del Chaco in Asuncion.
Cerro Porteno's defenders were caught ball watching as Tevez stepped in front of his opponent and glanced a header into the far corner for his fourth goal of the Copa Libertadores campaign.
And after Luis Leal's 56th-minute penalty was saved by Agustin Orion, Uruguay international Nicolas Lodeiro went up the other end and doubled Boca's lead four minutes later.
Cecilio Dominguez set-up a nervy finale after scoring a penalty six minutes from the end but Boca held on.
Meanwhile, Sao Paulo routed Mexican visitors Toluca 4-0.
Ricardo Centurion netted a brace for Sao Paulo, while Toluca forward Ernesto Vega was sent off with two minutes remaining.