Beverley Callard is to leave Coronation Street next year.
The actress, who took a five-month break in 2009 as a result of depression, said she was looking forward to "new challenges".
Bev first joined the series as Liz McDonald 21 years ago although she had a five-year absence until 2003 when she concentrated on theatre and her fitness DVDs.
Street bosses said they are working on an "exciting" exit storyline.
She said: "I've loved every minute of my second stint on the street, it's always a difficult decision to make the leap but I returned for the 40th so leaving for the 50th feels like perfect timing. I'll miss everyone on the show but I'm looking forward to some new challenges and to see what life has to offer beyond Liz's famous mini skirts."
The actress is to wed her long-term partner Jon McEwan at the end of this month and has been a regular guest panellist on Loose Women.
Speaking on the ITV1 on Wednesday, Bev described her decision to leave Coronation Street "for a while" as "one of the hardest ones I've ever made".
She added: "It's not because I'm disloyal, I love it, as you know, I'll always be loyal to the show. But as an actor, I just want to go back on stage again for a while and maybe do some other things.
"I'm getting married, as you all know, and I want some time with my new husband. But I will always be loyal."
Corrie producer Phil Collinson said: "Plans are now being made for an exciting exit storyline for her departure next year."