After an appeal for funds by the Royal College of Physicians of Edinburgh, the Edinburgh Infirmary, or Hospital for the Sick Poor, opened on 6th August 1729. It was the first voluntary hospital in Scotland.

At the time of opening the original building, the "Little House" at the head of Robertson's Close, contained four beds. A Royal Charter was granted in 1736, and in 1741 the Royal Infirmary of Edinburgh moved to new premises in what is now Infirmary Street. The building was designed by William Adam and accommodated 228 beds. The Infirmary gradually expanded to fill the whole area between Drummond Street and Infirmary Street, the two main additions being the old Surgical Hospital (opened in 1832) and the new Surgical Hospital (opened in 1853). By the 1860s concern was being expressed at the condition of the original building and at the cramped and smoky nature of the whole site. In 1872 David Bryce was commissioned to draw up plans for a new hospital, and in 1879 the infirmary moved to its site in Lauriston Place.

Until the inception of the National Health Service in 1948, the administration of the Infirmary was carried out by the Managers. They were responsible to the Court of Contributors, which consisted of subscribers contributing £5 or more to the Infirmary. Among the Managers were representatives from the Town Council, physicians and Surgeons, and the legal profession.

In 1948 the Infirmary became part of the Royal Infirmary of Edinburgh and Associated Hospitals group and was run by the Board of Management. From 1974 it formed part of the South Lothian District of Lothian Health Board as the Royal Infirmary of Edinburgh and Associated Hospitals Unit, and in 1994 became the Royal Infirmary of Edinburgh NHS Trust. In 1999 this in turn became the Lothian University Hospitals NHS Trust. The Hospital closed officially at 2.00am on 31st May 2003 and was moved to Little France. The move was the equivalent of moving a town the size of Galashiels!

The official opening of the new Royal Infirmary of Edinburgh at Little France took place on Thursday 9th October 2003. The Infirmary, which was granted a Royal Charter in 1736, was opened by HRH The Princess Royal.

Following the rediscovery and restoration of the Royal Charter, the Charter, Seal and Pouch were put on display. The Princess met with staff and invited guests. The Princess Royal also unveiled a plaque to commemorate the opening.