Four years later, and to many observers’ surprise, she was elected as the first woman ever to lead one of Germany's most powerful unions, succeeding Heinz Kluncker.

In 1994, Wulf-Mathies was – again unexpectedly – appointed as one of Germany's two European Commissioners by Chancellor Helmut Kohl; she succeeded Peter Schmidhuber.

After leaving the European Commission, Wulf-Mathies served as Executive Vice President Head of Corporate Public Policy and Sustainability at Deutsche Post from 2001 until 2009, working under the leadership of the company's CEO Klaus Zumwinkel.

In 2018, Wulf-Mathies was appointed by intendant Tom Buhrow to lead an internal investigation into allegations of sexual harassment at German public broadcaster Westdeutscher Rundfunk (WDR).

[9] When Home Affairs Minister Friedrich Zimmermann published memoirs in which he described trying to dampen her negotiating ardour by putting his hand on her knee, Wulf-Mathies demanded and obtained a retraction of the offending work from circulation.