He was Prime Minister of Rwanda from 1994 until his resignation in 1995, the first head of government appointed after the Rwandan Patriotic Front (RPF) captured Kigali.

However, in July 1993, MDR was split between two factions headed by Nsengiyaremye and Twagiramungu, who both wanted to be the Prime Minister in the anticipated Broad-Based Transitional Government (BBTG), a post which was to be decided prior to the signing of the Arusha Accords.

[12] In July 1994, Twagiramungu finally became Prime Minister in the Arusha-inspired "Government of National Unity" set up by the RPF after taking power in wake of the Rwandan genocide.

According to the historian Gérard Prunier who has discussed the issue with Twagiramungu at length, "The Hutu ministers were so conscious of the potential catastrophe their eventual resignations could cause that they swallowed it all in the name of national unity.

"[15] The tension within the administration came to a head when Twagiramungu called for an "extraordinary council of ministers on security matters" which met on 23 August 1995 and ended two days later when Paul Kagame—the de facto leader of Rwanda and the RPF—made a sardonic comment and left the room.

[3] In Brussels in March 1996, Twagiramungu and Sendashonga set up an exiled opposition party called the Democratic Forces for Resistance (FRD).

[19] In 1998, FRD invited four other exiled movements (RDR, GID, RNLM and UNAR) to form the Union of Rwandan Democratic Forces (UFDR), which wanted to press for a new power-sharing agreement along the lines of the Arusha Accords, and Twagiramungu was slated to be its president from 1998 to 2002.

[21] He was also unpopular with the old guard of the RDR "because of his leading role in the Rwandan opposition to Juvénal Habyarimana's government and his position in the moderate section of the MDR.

[22] Running on a platform of full employment, regional security, and progressive taxation,[23] he accused the government of attempting to silence his views.