Ian Duncan Smith should have remained in the Cabinet and fought against the controversial cuts to Personal Independence Payments from his position as minister, Boris Johnson has said.
"It would have been much better quite frankly if he had stayed in and fought his point of view from within the cabinet," he said.
"That's always the best thing."
Iain Duncan Smith's resignation has highlighted infighting within the Conservatives over budget plans to cut PIP.
I think Iain really cares about this stuff he wants to help the poor get out of poverty traps.
Asked if PIP cuts were a mistake Mr Johnson said: "I think I have already said very clearly that the government has decided collectively and quite rightly to take the PIP aspect of it [the budget] and try to sort it out."
Despite the row, the London mayor said the Conservatives were still a party that intended to help "all people".
Also on The Agenda, Mr Johnson will discuss his support for Brexit and how he was once mistaken for US Republican presidential hopeful Donald Trump.
Other guests on tonight's programme are Mariella Frostrup, Rory Bremner and Jane Moore.