Guarani hold the upper hand against Corinthians after claiming a 2-0 win in their home leg of the Copa Libertadores' last 16 on Wednesday.
Second-half goals from Federico Santander and Alberto Contrera lifted the Paraguayan hosts to victory at Estadio Rogelio Lorenzo Livieres in Asuncion.
Guarani were unable to impact the scoreboard during the opening half but they finally breached the Brazilian giants after the break, firstly through Santander, who benefited from a goalkeeping howler on the hour-mark.
Santander struck a low free-kick at Cassio but a seemingly routine save was bundled over the line by the Corinthians shot-stopper.
Contrera put the result beyond doubt with eight minutes remaining after directing a shot across Cassio using the outside of his left boot.
Sao Paulo will also take a lead into their last-16 second leg following a 1-0 victory at home to fellow Brazilian side Cruzeiro.
Ricardo Centurion's low diving header from Bruno's cross in the 83rd minute caught out Cruzeiro goalkeeper Fabio and proved the difference at Estadio Cicero Pompeu de Toledo.
The other all-Brazilian affair saw Internacional leave Atletico Mineiro with a 2-2 draw.
Internacional twice surrendered a lead but will still be undoubtedly the happier of the two teams heading into the return fixture.
Former Porto and Lyon striker Lisandro Lopez put Inter ahead in the second minute but Douglas Santos restored parity 12 minutes later.
Visiting Internacional were ahead again in the 61st minute via Valdivia, who headed the ball into the net from close range, only for Leonardo Silva to snatch a draw for Miniero in the fourth minute of injury time.
