Uruguay's Defensor have lost seven of their past 11 matches in the Copa Libertadores, including a 1-0 defeat away to Universidad de Chile on the opening matchday, while Peru's Garcilaso stunned Cruzeiro 2-1 in the South American continental competition.
Ramon Rodriguez was critical to Garcilaso's win over Cruzeiro last week, setting up Ezequiel Britez's equaliser in the 52nd minute and then scoring the winner 10 minutes later.
Garcilaso backed up that win with a 1-1 draw against Sporting Cristal on Saturday in the opening round of the Copa Inca to remain undefeated in 2014.
If Garcilaso defeat Defensor on Wednesday they will have six points from two games and have taken a significant step towards qualifying for the next round.
Garcilaso are level with Universidad de Chile in Group Five with three points and a plus-one goal difference.
But with Universidad de Chile and Cruzeiro first set to play on February 25, Garcilaso can claim a three-point lead and a mental advantage over their Group Five rivals with victory at the Estadio Centenario in Montevideo.
Chile's Union Espanola and Independiente del Valle of Ecuador will begin their group stage campaign on Tuesday.
Independiente will welcome Espanola to Sangolqui having won just two of five matches this year, while the Chileans are winless in two games and have just a pair of victories to their name from seven fixtures in 2014.
A win will take either of them level with Botafogo on points in Group Two.
In other fixtures this week, Penarol will host Santos Laguna, Deportivo Cali will visit O'Higgins, Bolivar are set to take on Leon, Nacional Asuncion clash with Zamora and The Strongest face Universitario.
