He received his episcopal consecration on 11 January 1976 from Cardinal Giovanni Colombo, with Bishops Bernardo Citterio and Libero Tresoldi serving as co-consecrators.

Pope John Paul II created him Cardinal-Priest of Santi Giovanni Evangelista e Petronio in the consistory of 25 May 1985.

Biffi was one of the cardinal electors who participated in the 2005 papal conclave that selected Pope Benedict XVI.

According to a leaked diary, he received one vote on the fourth ballot[citation needed] and subsequently discovered it was of Joseph Ratzinger.

[2] In 2000, Biffi told a Bologna conference that the Antichrist would most likely be a prominent philanthropist promoting the ideas of ecumenism, vegetarianism, and pacifism.

[7] In 2007, Biffi expounded on many of his views by publishing Memorie e digressioni di un italiano cardinale (Memoirs and digressions of an Italian cardinal).