Emily Thornberry made the comparison after calling the Prime Minister's accusations about EU leaders trying to influence the general election “preposterous, paranoid and xenophobic”.
Cersei Lannister is a murderous queen from the Game of Thrones franchise and Richard Nixon is the only US president to have resigned from office.
Ms Thornberry said Ms May’s speech showed the Prime Minister was “wobbling” in the lead up to the 8 June ballot.
“For Theresa May to use the backdrop of Downing Street to make such preposterous, paranoid and xenophobic claims is ill-befitting the office of Prime Minister,” Ms Thornberry told The Guardian. "The only response from the British public should be to get her out of that office as soon as possible.
“She talks about strong and stable leadership, but at the first sign of difficulty in her talks with Brussels, she is wobbling and lashing out like some hybrid of Richard Nixon and Cersei Lannister.”
Ms Thornberry added that Ms May’s actions were getting in the way of the Brexit negotiations.
“Instead of alienating our European partners, and insulting them with these ludicrous accusations, she should be working to build effective relationships and make meaningful progress; that is the way to get the best deal for Britain,” she said.
In her speech outside Downing Street, Ms May tore into some EU leaders and officials and said Britain would not allow the "bureaucrats of Brussels to run over us".
"Britain’s negotiating position in Europe has been misrepresented in the continental press, the European Commission’s negotiating stance has hardened," she said.
The Prime Minister took no questions after her speech, which came after the German press gave an account of a meeting between Ms May and Jean Claude Juncker that portrayed the Prime Minister in an unfavourable light.
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