It is based on the real city of Bristol, where Casualty was formerly filmed, and is notionally located in the fictional county of Wyvern in South West England, not far from the border with Wales.

[5] By Series 2, a permanent interior set was built in a warehouse on Kingsland trading estate in the St. Philip's area of Bristol, close to where the exterior shots of the A&E and hospital were filmed.

[12] Holby expanded by adding "HolbyCare", a private healthcare ward led by Michael Spence adjacent to the existing Intensive Care Unit on the fifth floor (Series 10, Episode 14 "Stolen").

[14] Other wards of the hospital to be referenced include Berkley, Clifton,[15] Curie (disused),[16] Florence, Geraint Morris,[17] Hitchcock (psychiatric), Linnaeus,[12] Swift and St Clares as well as the paediatric, neonatal, burns and neuro ICUs.

Although the ambulance service was only seen in Holby City very rarely, Casualty has featured paramedic characters as a key part of the cast since the show's 1986 conception.