Between 1998 and 2001, Melandri was Minister of Cultural Heritage and Activities in the Centre-left coalition governments of Massimo D'Alema and Giuliano Amato.

Melandri played a role in forming the parliamentary intergroup on bioethics, which she coordinated for two years, focusing on topics such as artificial reproduction,cloning, and living wills.

She proposed several bills on adoptions, bioethics, assisted reproduction, and the prohibition of extradition to countries that practice the death penalty.

In 2000, she was invited by then United States president Bill Clinton as the European representative to the "White House Conference on Culture and Diplomacy".

In the Legislature XIX of Italy (2001–2006), Melandri was a member of the Foreign Affairs Committee, the Italian Parliamentary Delegation at the Council of Europe and at the Western European Union, and the Parliamentary Supervisory Board on RAI, the national broadcasting TV., She proposed several bills on cinema, the promotion of books and reading, and the protection and promotion of cultural heritage.

In 2005, she participated in the Alliance for Civilization promoted by the then Spanish and Turkish prime ministers José Luis Rodríguez Zapatero and Recep Tayyip Erdogan.