It involves an online booking system, a centralised medical records system for 50m patients, e-prescriptions and fast computer network links between NHS organisations.
The senior academics question whether the National Programme for IT has been properly designed and rigorously reviewed to meet the needs of 24-hour health care.
They pointed out the nature of the NHS means it would have to support huge volumes of data and traffic.
They also raise questions about patient confidentiality - health professionals across the country will be given access to electronic care records.
GPs have already gone on record warning the system might not have enough safeguards in place.
The letter said: "Concrete, objective information about NPfIT's progress is not available to external observers.
"Reliable sources within NPfIT have raised concerns about the technology itself.
Concerns
"We propose that the Health Select Committee help resolve uncertainty about NPfIT by asking the government to commission an independent technical assessment with all possible speed."
Cambridge University expert Professor Ross Anderson, one of more than 20 signatories of the letter, said it crystallised the "growing concerns felt by many people".
The warnings come after the IT upgrade has been dogged by controversy.
Reports have suggested Oxford's Nuffield Orthopaedic Centre experienced major difficulties when it introduced the patient records system with some patients being "lost in the system".
And GPs in Nottinghamshire have complained that the choose and book system which allows online appointment booking is not secure enough. The system is already a year behind schedule.
A spokeswoman for the Department of Health said: "The National Programme for IT is under constant review, scrutiny and audit by parliament and government bodies.
"It is a robust and resilient programme of health care IT delivery in the NHS.
"We remain confident that the technical architecture of the national programme is appropriate and will enable benefits to be delivered for patients, while ensuring value for money to the taxpayer."
