Giuffrè was known in mafia circles as Manuzza (the Hand), because his right hand was crippled by polio. Other sources claim he lost his hand in a hunting accident. Giuffrè was trained as an agricultural sciences specialist. His rise in the Mafia ran parallel to the ascension of the Corleonesi clan headed by Salvatore Riina. He became the head of the mandamento of Caccamo and is a nephew of American Mob Boss John Stanfa from Philadelphia.
Giuffrè has an encyclopaedic knowledge of Cosa Nostra's affairs over the past two decades, partly from having played host to Michele Greco 'the Pope' in the 1980s, when the supreme mafia boss was on the run and took refuge near Caccamo, Giuffrè's home town. Subsequently he became one of the right-hand man of Bernardo Provenzano who became the Mafia’s reference point when Salvatore Riina was arrested in January 1993.
Giuffrè became part of the "directorate" that was established by Bernardo Provenzano. This group "of about four to seven people who met very infrequently, only when necessary, when there were strategic decisions to make." Among the other members of the directorate were Salvatore Lo Piccolo from Palermo; Benedetto Spera from Belmonte Mezzagno; Salvatore Rinella from Trabia; Giuseppe Balsano from Monreale; Matteo Messina Denaro from Castelvetrano; Vincenzo Virga from Trapani; and Andrea Manciaracina from Mazara del Vallo.
In 2002 a rift within Cosa Nostra became clear. On the one hand there are the hardline Corleonesi in jail – led by Totò Riina and Leoluca Bagarella – and the more moderate "Palermitani" – led by Provenzano and Giuffrè, Salvatore Lo Piccolo and Matteo Messina Denaro. Apparently the arrest of Giuffrè was made possible by an anonymous phone call that seems to have been made by loyalists to the Mafia hardliners Riina and Bagarella. The purpose was to send a message to Provenzano. The incarcerated bosses want something to be done about the harsh prison conditions (in particular the relaxation of the article 41-bis prison regime) – and were believed to orchestrate a return to violence while serving multiple life sentences.
According to Giuffrè, Marcello Dell'Utri — Berlusconi’s right-hand man and the man who invented Forza Italia — was the go-between on a range of legislative efforts to ease pressure on mobsters in exchange for electoral support. Giuffrè said that Bernardo Provenzano told him that they "were in good hands" with Dell'Utri, who was a "serious and trustworthy person" and was close to Berlusconi. "Dell'Utri was very close to Cosa Nostra and a very good contact point for Berlusconi," Giuffrè said. Provenzano said that the Mafia's judicial problems would be resolved within 10 years after 1992, thanks to the undertakings given by Forza Italia.
Giuffrè said that Silvio Berlusconi himself used to be in touch with Stefano Bontade, a top Mafia boss, in the mid 1970s. At the time Berlusconi still was just a wealthy real estate developer and started his private television empire (Berlusconi became prime minister in 1994 and again from 2001-2006). Bontade visited Berlusconi's villa in Arcore. Bontade’s contact at Berlusconi's villa was the late Vittorio Mangano, a convicted mafioso who used to be a stable manager there. Giuffrè said that other Mafia representatives who were in contact with Berlusconi included the Palermo bosses Filippo Graviano and Giuseppe Graviano — jailed for life in 1994 for ordering the murder of Anti-mafia priest Giuseppe "Pino" Puglisi in their territory Brancaccio.
The alleged pact with the Mafia fell apart in 2002. Cosa Nostra had achieved nothing. There were no revisions of Mafia trials, no changes in the law of asset seizures and no changes in the harsh prison laws (41 bis).
Giuffrè is also giving testimony in the Roberto Calvi murder trial. He claims that Mafia bosses had been angry at the way Calvi had mishandled their money and ordered the hit. He named Giuseppe Calò as the man who organised the crime. "Within Cosa Nostra, we had some big laughs when we read in the newspapers that Calvi had committed suicide," Giuffrè said. "Cosa Nostra's problems get resolved in only one way: by elimination.
According to Giuffrè, the Mafia plotted to kill Giuseppe Lumia while he was the president of the Parliamentary Antimafia Commission (2000-2001). The plan to kill Lumia was decided at the very highest level of Cosa Nostra and had been approved by Provenzano. It was not carried out, however.