He entered the service of the Secretariat of State in 1970. He worked in the nunciature in Germany collaborating with Corrado Bafile, future cardinal, from 1970 to November 1974. He was a staff member of the Council for Public Affairs of the Church from November 1974. He was named counselor of nunciature on 1 January 1983. He closely followed the negotiations that led to the signing, in 1984, of the revision of the concordat between Italy and Holy See.
At a 2004 conference Lajolo said that perfect religious freedom does not exist in any country in the world: "Even in states in which the right to religious freedom is taken very seriously, perfection is missing, often because a concern for church-state separation leads to penalising religious activity in the public sphere." He went on to say that "government and taxation policies may limit the rights of parents to choose a religious education for their children or may penalise the charitable work of the church by not recognising its nonprofit status. Attempts to ban religiously motivated positions from public policy debates are also infringements on religious freedom." Lajolo and other speakers at the conference also voiced concern about the increasing threats to Christians in Iraq and in other countries with a Muslim majority following the U.S.-led invasion of Iraq.[3]
He submitted his resignation to Pope Benedict when he turned 75 in January 2010. His resignation was accepted on 3 September 2011, with Archbishop Giuseppe Bertello appointed as his successor as of 1 October 2011.