Manders served for the People's Party for Freedom and Democracy in the European Parliament from 20 July 1999 until 17 October 2013 as part of the Alliance of Liberals and Democrats for Europe. He got enough preferences votes during each of the three elections to be chosen independent of his list position. He left the People's Party for Freedom and Democracy to become the party leader for the 50PLUS party in the 2014 European Parliament election, but the party didn't get enough votes for a seat. Manders felt that his former party had switched too much toward the political right, he also agreed that the People's Party for Freedom and Democracy's decision to limit their MEP terms to three might have influenced his decision. As Manders already served three terms he would not be eligible anymore.During the 2019 European Parliament elections in the Netherlands, he once again ran for the 50PLUS party. This time, he won a seat. On 2 June 2020, Manders left 50PLUS and joined the Christian Democratic Appeal party.