Defending Copa Sudamericana champions Universidad de Chile could only manage a 2-2 draw against Ecuadorian side Emelec in the first leg of their last-16 tie.
Emelec claimed two away goals, potentially invaluable should the return game in three weeks' time also finish all square.
The visitors took the lead in the 17th minute, when Argentinian striker Luciano Figueroa finished off a Marcos Mondaini cross from the right, but Enzo Gutierrez equalised only two minutes later by heading in a Eugenio Mena delivery.
Four minutes before half-time, Marlon de Jesus profited from a mistake by Universidad defender Charles Aranguiz to put Emelec ahead again.
However, Sebastian Ubilla levelled up at 2-2 seconds after the interval after a cross by Jose Rojas.
Universidad de Chile coach Jorge Sampaoli was disappointed with the result, saying: "The team's form was not the best. The most worrying thing to me is to see the team play this way. We do not analyse the result, but the form. It is up to us, the coaches."
Emelec scorer De Jesus was happy with the result though, and although his side twice led he said: "The important thing is that we did not lose. We had opportunities to win, but failed, so we are hoping to play better in the second leg.''
De Jesus told Fox Sports: "We were surprised by the early goal in the second half. We must correct that for the return game, but the team showed attitude until the final whistle."
In Sao Paulo, Brazilian giants Palmeiras beat Colombia's Millonarios 3-1.
The early foot injury Palmeiras forward Maikon Leite suffered in the eighth minute did not affect the team as they took the lead four minutes later through Obina after good work from Daniel Carvalho.
Ten minutes after the interval, Tiago Real, who had replaced Marcio Araujo after the break, finished a Luan cross from the left to make it 2-0.
Millonarios reduced their deficit with Artur turning the ball into his own net in the 85th minute and the Colombian side were encouraged by that goal, but Palmeiras forward Luan then made the most of a terrible mistake by defender Pedro Franco.
Franco's misplaced pass was met by Luan who beat goalkeeper Luis Delgado to restore the two-goal margin in the 88th minute. The second leg will be played in Bogota on October 23.