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Holby City follows the professional and personal lives of surgeons, nurses, other medical and ancillary staff and patients at Holby General. It features an ensemble cast of regular characters, and began with 11 main characters in its first series, all of whom have since left the show. New main characters have been both written in and out of the series since. In addition, Holby City features guest stars each week, as well as recurring guests that take part in story arcs that span a portion of a series. Occasionally, the recurring guest storylines will span multiple series. Many actors in the series have made prior, minor appearances as both patients and staff members in both Holby City and Casualty - in some instances crediting these former appearances for their later casting as main characters in Holby City.

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In casting the first series of Holby City, Young selected actors who were already established names in the acting industry, primarily from a soap opera background. He cast Michael French as Nick Jordan, George Irving as Anton Meyer, Angela Griffin as Jasmine Hopkins, Lisa Faulkner as Victoria Merrick and Nicola Stephenson as Julie Bradford. Young explained: "Soap actors are the best actors. There's been so much snobbery before. The whole thing about typecasting was probably invented by actors who couldn't get other work. From day one I knew I wanted to put on screen people that viewers want to watch. There's no downside to that." This propensity for hiring established actors continued as the soap progressed, with later roles being awarded to comedian Adrian Edmondson, former film actress Patsy Kensit, and Jesus of Nazareth star Robert Powell. When Jane Asher was cast in the recurring role of Lady Byrne in 2007, Inside Soap magazine asked series producer Diane Kyle whether the production team intentionally sought out "well-known-names", or whether roles simply went to the actor best-suited for the part. Kyle responded: "It's lovely when we have a new member of the cast come in and bring an audience with them. But we want the best actors, and the star names we cast are always the best - which is why we go for them."

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Many cast members who play main characters have made previous appearances in Holby City and Casualty in minor roles. Amanda Mealing, who plays cardiothoracic consultant Connie Beauchamp, appeared as the mother of a paediatric patient in the show's fourth series. Luke Roberts, who plays registrar Joseph Byrne, appeared as the son of a medical professor in Holby City's seventh series, Rosie Marcel, who plays registrar Jac Naylor appeared in both Holby City and Casualty as a patient on three occasions. Stella Gonet, who plays CEO Jayne Grayson, had a minor role as an anaesthetist in Casualty, while Hari Dhillon, who plays general surgical consultant Michael Spence, previously appeared as a recurring anaesthetist in Holby City. In some instances, actors have stated that it was their guest appearances which lead to their casting in more permanent roles. Roberts believes that his single scene in series seven was enough for him to be called in for the part of Joseph, explaining: "I hear it got the attention of the producers. Amanda Mealing put a good word in for me that day as well." Conversely, Dhillon dismissed his minor role as Dr Sunil Gupta as a part he took immediately after leaving drama school, unable to even recall the year of his appearance.