Santos were once again defeated at altitude as a brace from Jhasmani Campos guided Bolivar past the reigning champions with a 2-1 triumph at the Estadio Hernando Siles.
The Peixe had already tasted defeat inside the ground in the group stage of this season's competition when they were beaten by The Strongest, and their last 16 tie with La Academia could not have got off to a worse start. Within two minutes the hosts were ahead as Campos' thunderous free kick hit the post but ricocheted off the back of Rafael and into the net.
Santos were playing much of the game on the break as Bolivar sought to create opportunities to shoot from distance. The Brazilians managed to pull level in the 34th minute with some help from their own free kick specialist. Elano's effort from the dead ball was tipped onto the post by Marcos Arguello but Maranhao stormed in to slam the loose ball into the net. The former Manchester City midfielder worried Arguello again with a ferocious free kick struck from just outside the centre circle shortly after the break but the keeper managed to stop the swerving effort from finding the bottom corner.
Bolivar controlled possession throughout the second half as Santos' senior players began to struggle to compete at altitude. La Academia were finally rewarded after 75 minutes when Campos found the bottom corner with a sweetly struck free kick from 35 yards out.
Muricy Ramalho's men now face the task of overturning the deficit at the Vila Belmiro in a a fortnight if they are to retain their crown.
Internacional failed to make the most of home advantage as they were held to a draw by their Brazilian rivals in Porto Alegre. Jesus Datolo had the best chance to put the hosts ahead, but the Argentine missed his penalty to keep the score goalless. Read the full match report here.