Lord Kerslake has resigned as the chairman of a major London hospital trust because of NHS funding problems.
The former head of the civil service says the government is being unrealistic about the challenges facing the health service.
He announced he was stepping down as chairman of King's College Hospital NHS Foundation Trust on Sunday.
NHS Improvement described the hospital's financial performance as "unacceptable".
A spokeswoman added: "It is the worst in the NHS and continues to deteriorate."
In a statement, Lord Kerslake said of his decision to quit: "I do not do this lightly as I love King's but believe the government and regulator are unrealistic about the scale of the challenge facing the NHS and the trust.
"I want to pay tribute to the staff and their excellent patient care."
The House of Lords peer also paid tribute to the "world-class" care given at the hospital, especially after the Westminster and London Bridge terror attacks, in a self-penned Guardian article.
He added: "There are undoubtedly things that I and the trust could have done better, there always are, but fundamentally our problems lie in the way that the NHS is funded and organised."
Analysis: BBC health correspondent Hugh Pym
Lord Kerslake's comments come after the board of NHS England said targets for waiting times could not be met next year even with the extra money allocated in the Budget.
Coming from a figure with such high level Whitehall experience the latest criticism of the government's handling of the NHS carries some weight.
King's College Hospital has been in long-running discussions with the regulator NHS Improvement about reducing its deficit.
It's understood that it was close to being put into a financial special measures regime in which NHS Improvement staff would work alongside hospital management.
Labour's shadow health secretary Jonathan Ashworth said the resignation was "embarrassing for the government".
King's College Hospital described Lord Kerslake as a "passionate advocate and champion" of the trust who had a "heartfelt commitment to staff and patients".
It added that he had led King's "through a challenging period which has also seen some notable successes, our response to three major incidents in London, the launch of the helipad and delivering some of the highest patient outcomes of any Trust in the UK".
NHS Improvement said it respected Lord Kerslake's decision to step down and would "replace him with a highly experienced new chair to take charge of the trust's position".
A Department of Health spokeswoman added: "We know that King's NHS Foundation Trust faces huge financial challenges and we will support them to tackle these issues and continue to deliver high quality care for patients under a new chairman."
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