Guy's and St Thomas' hospitals will both have new addresses from Monday 7 January - but no department or ward is moving.
The £500,000 project – part-funded by Guy's and St Thomas' Charity – aims to eliminate years of confusion between the two hospital sites.
Every year hundreds of patients miss appointments after arriving at the wrong hospital.
The official postal address of Guy's Hospital is currently St Thomas' Street – whilst St Thomas' Hospital's address is Lambeth Palace Road, which is the accident & emergency entrance and not the main entrance.
The names of the main buildings at Guy's Hospital are also being changed to make it easier for patients to find their way to the right department.
• Guy's Tower will become Tower Wing
• Thomas Guy House will be split into Southwark Wing and Bermondsey Wing
• New Guy's House will become Borough Wing
• The area which houses the Minor Injuries Unit and Oncology Outpatients will be the Tabard Annexe
Internal physical improvements are also taking place with the introduction of colour-coded schemes for the wings of the hospitals.
Guy's and St Thomas' NHS Foundation Trust is also introducing new signage, which will reflect the new names at Guy's, as well as new signage at 'wing' entrances, large maps at each main entrance and at each wing entrance there will be alphabetical directories of departments.
The trust is also moving to use more patient-friendly terms in its signage with Paediatrics and Ophthalmology changing to Children's Services and Eye Department respectively.
"We are committed to improving the experience of patients and to delivering the best possible care," explains chief nurse Eileen Sills.
"Helping patients to find their way to our hospitals, and around the sites once they arrive, is a key part of this commitment. We also hope this will significantly reduce the number of missed appointments.
"These changes will make visiting the hospital an easier and more straightforward experience for patients, and their friends and family."
For the latest local news and events direct to your inbox every Monday, you need our weekly email newsletter SE1 Direct.
7,000+ locals read it every week. Can you afford to miss out?
Read the latest issue before signing up