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Mezzasoma had to contribute to his impoverished family's income from early on, and took several jobs before finishing studies in accounting. A secretary to the lawyer Amedeo Fani, he was integrated to the state bureaucracy in 1929, after Fani became undersecretary to the ministry of Dino Grandi (the Minister of Foreign Affairs). In 1931, he joined the ranks of the National Fascist Party (PNF), and soon after became secretary of the Perugia branch of the Gruppo Universitario Fascista (GUF), the Fascist student organization.
The following year, Mezzasoma was appointed one of the local PNF leaders in Perugia (holding the position until 1935). He began writing for official magazines, such as Dottrina Fascista and Roma Fascista, usually under the pen name Diogene. Editor of Assalto in 1934, he became co-editor of the GUF mouthpiece Libro e Moschetto; in 1937, he published Essenza dei GUF ("Essence of the GUF"), a propaganda volume that was distributed throughout the network of Fascist youth organizations.
A national deputy-secretary of the GUF in 1935, he was included to the leadership group of the PNF in January 1937, and its deputy-secretary on February 23, 1939. When Italy entered World War II as an Axis Power, he volunteered for the 7th Artillery Division. In 1942, he quit the army to become the director of the Italian press; he continued in that role until 1943. Unlike a great many leading figures of the government (such as Galeazzo Ciano and Dino Grandi), he stayed loyal to Mussolini long after the July 1943 Grand Council of Fascism crisis which ended the latter's rule in Rome.
With the foundation of the Nazi Germany-assisted Italian Social Republic, he was appointed Mussolini's Minister of Popular Culture, and held this post until the Republic collapsed less than two years later.
He clashed with Junio Valerio Borghese and, on April 19, 1945, left for Milano - parting with his collaborators (including Giorgio Almirante). It seems that he had the opportunity to flee the region following Germany's defeat, but would have refused, saying: "I am a minister of Mussolini, I shall die with him".