The unions representing nurses and midwives have joined others in stating their "outright opposition" to the government's NHS plans in England.
The Royal College of Nursing and the Royal College of Midwives had expressed concerns in the past, but said they were willing to work with ministers.
However, now they want the entire bill covering the changes to be dropped.
Health Secretary Andrew Lansley said the unions wanted to "have a go" at government about "pay and pensions".
The colleges' stance comes after a similar move by the British Medical Association last year.
It also mirrors the stance adopted by Unison, which represents a host of administration and support staff, such as porters.
But what impact this intervention has remains to be seen.
The Health and Social Care Bill is still working its way through Parliament, and the bill is in the Lords at the moment.
In many ways it is over the worst political hurdles and it seems the only way it could be stopped would be if the Lib Dems blocked it when it returns to the Commons - but that is considered unlikely.
On the ground, changes are already being made to pave the way for the new system to kick in, in 2013.
For example, while the doctors union is against it there has still been enough GPs coming forward to pilot the new plans in 97% of the country.
Anger
Under the plans, GPs are being put in charge of much of the NHS budget, while the health service is being opened up to greater competition from the private and voluntary sector.
In June the government announced a series of changes to the original proposals in the face of mounting opposition.
These included giving health professionals other than GPs more power over how NHS funds were spent, as well as watering down the role of competition.
The health unions initially gave the changes a cautious welcome, but they have been left disappointed by the finer details that have emerged during the parliamentary process.
One of the key developments was the news, which emerged just after Christmas, that NHS hospitals would be allowed to do 49% of their work in the private sector.
Peter Carter, general secretary of the RCN, which represents 410,000 nurses, midwives, support workers and students, said: "The RCN has been on record as saying that withdrawing the bill would create confusion and turmoil, however, on the ground, we believe that the turmoil of proceeding with these reforms is now greater than the turmoil of stopping them.
"The sheer scale of member concerns, which have been building over recent weeks, has led us to conclude that the consequences of the bill may be entirely different from the principles which were originally set out."
Cathy Warwick, of the RCM, said: "The government has failed to present sufficient evidence that its proposals are necessary. They have failed to present evidence that the upheaval will result in an improvement in services to the people of England.
"And they have failed to answer the concerns of the people who fear for the future of the NHS under these plans."
Savings plans
Both unions also expressed concerns that the changes were compromising the ability of the NHS to make the £20bn of savings it has been asked to make by 2015.
Mr Lansley said that nurses had previously been "right at the heart" of the process of planning reforms to the NHS to deliver better care for patients.
"The only thing that has happened in the last few weeks that has led to this situation with the Royal College of Nursing, is that the two sides of the Royal College of Nursing have shifted," he told BBC Breakfast.
"They used to be a professional association that was working with us on professional issues, and will carry on doing that, but now the trade union aspect of the Royal College of Nursing has come to the fore.
"They want to have a go at the government - and I completely understand it - they want to have a go about things like pay and pensions."
A Department of Health spokesman said: "The bill is needed to empower doctors, nurses, and other front-line healthcare workers across the NHS to take charge of improving care.
"We will continue to work with nurses and all other health professionals to ensure that the NHS delivers the best possible care for patients."
Shadow health secretary Andy Burnham said it was time to scrap the bill.
"A reorganisation on this scale needs a professional consensus for it to succeed. A year since the bill was introduced, it is abundantly clear that the government's plans do have failed to build that."
Analysis
The move by the two unions is unlikely to see the bill stopped in its tracks.
But it is clear the government's relationship with NHS staff is fracturing, possibly beyond repair.
Some inside government were saying the move by the royal colleges was being driven by their dissatisfaction over pensions.
That has undoubtedly played a role. So too has the drive to make £20bn of savings by 2015 - the equivalent of 4% of the budget a year.
This is putting more and more pressure on hospitals and waiting times in particular.
It means there is a toxic cocktail brewing inside the health service - and this spells trouble for the government.
It came to power saying - in private at least - that the NHS was its good news story, but all too often it is finding the headlines are negative.
