At least 22 "potentially serious" incidents - three involving deaths - have been recorded in connection with the new NHS 111 advice line, it has been reported.
Two deaths are being investigated in the East Midlands, and one in the West Midlands, while a further 19 possible incidents have also been recorded, health magazine Pulse said.
NHS England will now carry out a review into the "unacceptable" performance of some local providers of the urgent care line, which launched just weeks ago.
The investigation comes with hospital emergency departments bracing themselves for a busy bank holiday weekend, as doctors voiced concern about whether the new advice line could cope.
Patients have been complaining about calls going unanswered and poor advice being given, especially at weekends, which has led to hospitals being inundated with patients who could be treated elsewhere.
The deaths being looked into include a 47-year old who died from a suspected overdose after relatives contacted NHS 111 requesting mental health assistance, and an 83-year-old who died after calling the line about severe abdominal
pain, Pulse reported.
A spokesman from Derbyshire Health United - which covers NHS 111 in Derbyshire, Nottinghamshire and Northamptonshire - said it was investigating the two deaths but that so far it believes the system and processes that were followed would have been "exactly as expected".
NHS Direct - which covers eight NHS 111 areas - said it is investigating the unexpected death of a patient who called the advice line and was referred to a GP out-of-hours service in the West Midlands, Pulse reported.
NHS England's board members voted to set up a review into the service.
''The performance standards which have been introduced for NHS 111 represent a gold standard which the majority of NHS 111 services in England are now meeting, though in some areas performance is still unacceptable, especially at weekends", a spokesman said.
''Some local providers of NHS 111 have not provided the prompt, reliable service the public need and want. NHS England's board is determined to ensure that the public have access to a gold standard NHS 111 service wherever they live in England.
''The NHS 111 service was introduced to deal with public concern and frustration in accessing NHS care, especially at weekends and out of hours."
Dr Taj Hassaan, vice president of the College of Emergency Medicine, who works in Leeds, told the Daily Mail: 'We're worried that this is the first bank holiday following the launch of 111. At a time where 111 in parts of the country is fragile, we need to plan as well as we can.'
The college said it has noted the "very serious concerns" being expressed about the efficiency and effectiveness of NHS 111 around the country.
''We have strong reservations and concerns about the amount of investment that has gone into providing clinical support to the computerised decision algorithms being used to help the public seek the service that is most appropriate to them," a spokesman said.
"This is leading to a default to the ultimate safety net of the NHS with the public being directed to attend their emergency department.''
The college estimates that 15% to 30% of A&E traffic could be treated by other healthcare professionals such as GPs.
It has urged hospital trusts to ensure they have enough resources to cope with demand for urgent care over the bank holiday weekend.
Gordon Miles, chief executive of the college, encouraged patients to use their judgment about whether or not to go to hospital.
Clare Gerada, chairwoman of the Royal College of General Practitioners (RCGP), shared the concerns about the advice line, which has been rolled out to nearly 90% of the country and replaces the former NHS Direct line.
''It is extremely worrying that there is still so much uncertainty around the delivery and reliability of the advice provided by NHS 111 in some areas.
''We are also concerned that patients are losing confidence in the new service before it is even fully up and running.
''We call on NHS England to provide more reassurance about its effectiveness and ability to deliver the necessary standards of care for all patients using the service, right across England.''
Calls to NHS 111 from landlines and mobile phones are free, and the service is available 24 hours a day, 365 days a year.
A Department of Health spokesman said: ''We know that there is pressure on urgent care services and this isn't just about A&E, it's also about how the NHS works as a whole, and how it works with other areas such as social care.
"We are in discussions with NHS England and others to see how best to get long-term solutions to a long-term problem."
An NHS England spokesman said: "The safety of patients must be our paramount concern and NHS England will keep a careful eye on the situation to ensure NHS 111 provides not only a good service for the public but one which is also safe."