For the 2010, 2012 and 2017 general elections, Pechtold served as lead candidate again, and following a successful cabinet formation in 2017 with the People's Party for Freedom and Democracy (VVD), the Christian Democratic Appeal (CDA) and the Christian Union formed the third Rutte cabinet, with Pechtold opting to remain as Parliamentary leader.

Pechtold resigned as chairman and mayor the same day that he took office as the new Minister for Government Reform and Kingdom Relations, on 31 March 2005.

The next day, Prime Minister Jan Peter Balkenende offered the resignation of the full cabinet to Queen Beatrix.

For the 2010 general election, Pechtold again as lead candidate won ten seats but the Democrats 66 remained an opposition party.

With the following 2012 general election, Pechtold again as lead candidate won two seats with the Democrats 66 again remaining an opposition party.

After the 2010 general election, the D66 won seven seats in the House of Representatives which journalists claimed was due to Pechtold's leadership during the fourth Balkenende cabinet time.

In 2012, Pechtold published Henk, Ingrid, & Alexander, which ostensibly aimed to break through the populism that had dominated Dutch politics in the previous decade, "Henk" and "Ingrid" being the generic names proposed by Geert Wilders and other Party for Freedom politicians to represent the average Dutch couple, by engaging everyday people in conversation.

[3] After the shootdown of Malaysia Airlines Flight 17 in July 2014, Pechtold explicitly voiced his support for economic expediency over ethical correctness by stating: "We are a small country, dependent on our exports, and unlike the United States, we cannot always react from our moral high grounds.

"[4] In December 2017, it was revealed that Pechtold received an apartment valued at 135,000 euros from Serge Marcoux, a former Canadian ambassador, that was not listed on the gift register of the House of Representatives, with Pechtold justifying the lack of report by saying that he knew Marcoux from outside politics and that the apartment was a private gift which did not fall under the purview of the register.

[8][9] From March 23, 2021, Pechtold presents the TV program De Achterkant van het Gelijk for broadcaster BNNVARA on NPO 2.