[5] The first hospital building on the Grosvenor Road site was designed in 1899 by architects Henman and Cooper of Birmingham[6] in a partial adoption of the English Revival style.

There were little yellow Xs and Ys detailed for X- and Y-chromosomes, and portraits (laser-cut in sheet steel) chart the progress of a human life from birth to the age of 100.

[14] The Prince of Wales opened a new 400 bed, seven storey building, which incorporated new intensive care and fracture units built at a cost of £42 million,[15] in September 2003.

[18] However, due to construction difficulties, the project was understood to be running at least eight years late,[19] and it was announced in October 2020 that the opening would be delayed indefinitely.

During his time at the Royal, Pantridge developed the portable defibrillator, which revolutionised emergency medicine by allowing patients to be treated early by paramedics.

Gunshots to the knee (associated with paramilitary punishment attacks in Northern Ireland) enabled surgeons at the hospital to gain renown with their treatment of such injuries.