Between 1974 and 1989 Zigiranyirazo served as governor of Ruhengeri. An ethnic Hutu, he was well-connected to the Hutu establishment of politicians, businessmen and military officers which then controlled Rwanda: he is the brother of Agathe Kanziga, wife of the late Rwandan president Juvénal Habyarimana, whose assassination on April 6, 1994 precipitated the events leading to the genocide.
In 1989 he resigned his position as prefect to study at the Université du Québec à Montréal (UQAM) in Montreal, Quebec, Canada. He was expelled from UQAM and from Canada in 1993 after being convicted of uttering death threats against two Tutsi refugees in Montreal, who "accused him of participating in the planning of ethnic massacres."
Zigiranyirazo returned to Rwanda following his expulsion from Canada. The Office of the Prosecutor of the International Criminal Tribunal for Rwanda (ICTR) has accused him of committing several crimes during the months of the genocide in 1994. Specifically, ICTR alleges that Zigiranyirazo "ordered or authorized roadblocks to be established in direct proximity to each of his three residences ... knowing and intending that they would be used in the campaign of extermination and killing."
Further "Protais Zigiranyirazo further instructed men at the roadblock to kill all Tutsi that attempted to pass through. Shortly thereafter, and on a continuing basis, soldiers and Interahamwe killed a number of people in their homes and killed people identified as Tutsi that attempted to pass through the roadblock."
On his initial appearance before the court in October 2001 he was charged with two counts of crimes against humanity. The indictment against him was, however, amended pending his second appearance on November 25, 2003. The amended indictment accuses him of committing genocide against Tutsis between April and July 1994 in Kigali and Gisenyi.