The Brazilians face the added challenge of the rarefied atmosphere at the once-rich, silver-mining city of Potosi on the Andean plateau in Wednesday's first leg as they look to qualify for the group stage from one of six preliminary ties.
Brazilian sides were among the most vociferous opponents of matches at high altitude when FIFA looked into banning them, a move that met with strong opposition from Andean nations such as Bolivia and Ecuador.
Cruzeiro, continental champions in 1976 and 1997, will be looking to emulate holders Estudiantes, the Argentine side who beat them 2-1 away in the second leg of the 2009 final to win their fourth title.
Juan Sebastian Veron's Estudiantes last year became the first team to lift the trophy having started from the preliminary round.
Cruzeiro landed in that round after finishing fourth in the 2009 Brazilian championship behind Flamengo, Internacional and Sao Paulo, who went directly into the group stage which starts next month.
Also taking part are Copa Brasil winners Corinthians, the only Brazilian entrants never to have won the title, who have brought former Real Madrid team mates Ronaldo and Roberto Carlos together in a bid to end that drought in their centenary year.
BIG-TWO FAILURE
Estudiantes, who lost the Club World Cup final to Barcelona in Abu Dhabi last month, go straight into the group stage.
The Argentine teams in the preliminary round are twice runners-up Newell's Old Boys, who meet Emelec of Ecuador away in their first leg on Wednesday, and newcomers Colon, who are at home to Chile's Universidad Catolica on Tuesday.
Argentina's "big two", twice champions River Plate and six-times winners Boca Juniors, are not even in this elimination round, their poor league form last year excluding them from the competition as a pair for the first time in 15 years.
Instead, first-time Argentine league champions Banfield are in the group stage with 1994 winners Velez Sarsfield and Lanus.
Also missing are the great Penarol of Uruguay, five times winners and recently named by FIFA historians as the outstanding South American team of the 20th century.
Their Montevideo arch-rivals Nacional, champions three times and semi-finalists in 2009, will be there in the group stage.
Five Mexicans teams from the rival CONCACAF confederation are taking part: champions Monterrey, Estudiantes and Morelia starting at the group stage and Guadalajara and San Luis having a bye into the first knockout round.
Guadalajara and San Luis were given invitations having suffered the consequences last year of the H1N1 flu virus outbreak in Mexico.
They withdrew from the 2009 competition when their South American rivals Sao Paulo and Nacional accepted the option of not travelling to Mexico for the first legs of their ties in the round of 16.
