The case for improving hospital care at weekends in England is "simply unassailable", medical chiefs say, as new figures on deaths are published.
NHS England medical director Sir Bruce Keogh called for action as research by him and others linked the "weekend effect" to 11,000 excess deaths.
It is not clear exactly how many of these could have been avoided.
But the study in the British Medical Journal said the findings raised "challenging questions" about weekends.
The study has been published as the government is trying to push ahead with its policy of extending the services available seven days a week.
The research - carried out by seven leading doctors and statisticians, including Sir Bruce - looked at hospital records during 2013-14.
It follows on from similar research published three years ago.
NHS weekend: Want to know more?
- Visit the BBC's special report page on 7-day services (This link will not work on the BBC app but some of the key content can be seen below)
- Nick Triggle: Does a Monday to Friday culture exist in hospitals?
- 'My long weekend as a consultant'
- What you need to know about 7-day care
- The picture in the rest of the UK
During the year studied, 15.9m patients were admitted to hospital and just over 290,000 - 1.8% - of them died within 30 days.
But when the data was broken down by day of admission a clear "weekend effect" was identified.
An admission on Fridays led to a 2% increased risk of death, on Saturdays it was 10%, on Sundays 15% and Mondays 5%, the study said.
Combined, this equated to 11,000 excess deaths over the course of the year.
Researchers adjusted the data to take into account factors such as the age of patients and their levels of illness - patients admitted at weekends tend to be sicker because non-emergency work, such as knee and hip operations, tend not be done, while community services are less available.
But they said it was impossible to know whether this process had managed to take into account these factors entirely and so it would be "misleading" to conclude all these excess deaths could have been avoided.
Is this death rate worse than previously thought?
No. It reinforces what has been said before. In July, when Health Secretary Jeremy Hunt set out his intentions on seven-day working in hospitals he talked about 6,000 deaths.
That was based on the previous study by these authors, which was published in 2012.
The higher risk of death at weekends was almost exactly the same in the two studies - 16% on Sundays last time compared with 15% in the latest one and 11% on Saturdays compared with 10%.
The reason why the absolute number is different is because the 6,000 figure was just based on Saturday and Sunday while this one includes Friday and Monday. What is more, the total number of admissions and deaths is increasing, partly because of the ageing population.
But this report does contradict the health secretary in one respect. He talked about the deaths being avoidable, while the researchers say you cannot be so categorical.
Nonetheless, Sir Bruce said he believed it presented a compelling case for action.
"Doctors up and down the country routinely go the extra mile, well beyond any contractual duty, to save and improve lives. But the idea that patients are being harmed because of the way we organise our services is quite simply beyond what any of us can regard as acceptable.
"The moral and social case for action is simply unassailable and there is widespread clinical consensus about that. Change always brings practical difficulties that must be tackled but we cannot duck the facts."
While emergency care from A&E units to life-saving surgery is available at weekends, staffing levels are much lower and access to key tests is more difficult than it is during the week.
Ministers have identified the opt-out consultants have in their contract meaning they do not have to do non-emergency work at weekends as a key barrier to improving care.
They have given the British Medical Association a deadline of next Friday to agree to talks about removing it - or they will impose the change on new doctors.
BMA leader Dr Mark Porter said: "Given the current funding squeeze on NHS Trusts, the only way for many hospitals to increase the number of doctors over the weekend would be to reduce the number providing care during the week.
"If the government really want to deliver more seven-day services then they need to show patients, the public and NHS staff their plan for how this will be delivered at a time of enormous financial strain on the NHS and when existing services and staff are under extreme pressure."
Chris Ham, chief executive of the King's Fund think tank, said there was a need to be "cautious" about the causes behind the excess deaths, but he admitted it would give "further impetus".
Health Secretary Jeremy Hunt said the findings should act as a "wake-up call".