Amanda Burton is returning to Silent Witness to mark the show's 25th series in 2022.
The 64-year-old actress was the original star of the long-running crime drama, appearing as Sam Ryan for 54 episodes from 1996 until 2004, when the character returned to Northern Ireland to be with her family.
Now Sam will make a dramatic return after an 18-year absence in a new six-part series, linking up with regular team members Emilia Fox (Nikki Alexander), David Caves (Jack Hodgson) and Genesis Lynea (Simone Tyler) for a "monumental story".
"I am so excited to be returning to Silent Witness and stepping back into Sam Ryan's shoes - with a difference!" said Burton.
"Audiences can look forward to plenty of twists and turns as they discover what Sam's been doing since leaving the Lyell."
Fox - on the show since 2004 - added: "It is such a delight and thrill to be working with Amanda. To have Sam Ryan back again at the heart of the show is the greatest way of all to celebrate the 25th anniversary of Silent Witness."
Exec producer Lawrence Till said: "I am delighted that Amanda agreed to return to Silent Witness for its Silver Anniversary.
"Silent Witness has a large and loyal audience and remains as popular as it has ever been with audiences regularly consolidating at over six million viewers.
"It is fantastic to have Sam Ryan at the centre of the series again alongside our other Lyell characters for a monumental story told in six parts."
Filming on the new six-part series is already thought to be underway.