The draw for the Copa Libertadores round of 16 took place in Paraguay on Monday.
Defending Copa Libertadores champions River Plate will face Cruzeiro in the last 16, while last season's runners-up Boca Juniors are set to meet Athletico Paranaense again.
River's quest for back-to-back titles will continue against Brazilian giants Cruzeiro in a two-legged round-of-16 clash starting in July.
After edging Argentine rivals Boca in a dramatic final last season, River advanced to the knockout stage as runners-up to Internacional in Group A.
Meanwhile, two-time champions Cruzeiro – who last won the competition in 1997 having reached the final in 2009 – finished six points clear atop Group B.
Monday's draw in Paraguay also has two other mouth-watering ties pitting Argentina against South American rivals Brazil.
Six-time champions Boca will play Brazil's Paranaense – who won the Copa Sudamericana last year – after the two teams went head-to-head in Group G.
Boca finished two points clear of Paranaense, who won the first meeting 3-0 in Curitiba before the Argentine giants sealed top spot with a last-gasp 2-1 victory in Buenos Aires on matchday six.
The other Argentina-Brazil fixture will see Godoy Cruz take on Luiz Felipe Scolari's Palmeiras.
Copa Libertadores last-16 draw:
River Plate v Cruzeiro
Godoy Cruz v Palmeiras
Emelec v Flamengo
LDU Quito v Olimpia
Athletico Paranaense v Boca Juniors
Nacional v Internacional
Gremio v Libertad
San Lorenzo v Cerro Porteno
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