Mr Donald stepped down in the autumn of 2011 following a series of disputes with the hospital board before returning to his desk just before Christmas that year.
But this time it appears the break is permanent and Mr Donald said tonight:
"For now, I am looking forward to spending more time with my family over the festive period before starting a new work venture in the New Year."
Alistair Flowerdew, medical director at the Royal Berks for 13 months, will take over as Acting Chief Executive until a new appointment is made. He was formerly Medical Director of the Golden Jubilee National Hospital and Salisbury NHS Foundation Trust.
Mr Donald said: “It has been a privilege to be the Chief Executive of the Royal Berkshire, which is a good Foundation Trust, with great staff and local support.”
The Trust, he said, is strategically well placed to become a major emergency centre. At the same time local services in Reading, Newbury, Henley and Bracknell are proving to be more popular than ever with patients and GPs.
Mr Donald said: "Patient and staff experience feedback remains high and the Trust continues to be amongst the first major district general hospitals to bring the latest medical breakthroughs into practice.
"This is quite an achievement in a health system that is amongst the lowest per head of population funded. Achievements only made possible through the dedication, commitment and teamwork of all staff across the Trust and West Berkshire."
He added: "We have positive working relationships with our partners across Thames Valley and the Oxford Academic Health Science Centre. We benefit from a long tradition of strong partnership work with our local GPs, health and social care partners and this will continue to be critical to the success of the Trust in the years ahead.
Mr Donald said: "I wish every member of the Royal Berkshire team well and look forward to watching the Trust go from strength to strength. I will miss catching up with frontline teams and patients.
"Learning about and supporting the life saving and life changing work we do every day made being Chief Executive, one of the most complex and challenging roles in the public sector, worthwhile. "
Royal Berks trust chairman Stephen Billingham said: "We have greatly valued Ed's contribution and personal commitment to the NHS and our Trust. I am sure the whole Trust will join me in wishing him well for the future."
***Full reaction in your Boxing Day Chronicle