Chris Fountain and Jamie Lomas, who play the show's resident bad boys Justin Burton and Warren Fox respectively, will bow out in a storyline which sees their characters caught in a fire at The Loft.
Warren's past comes back to haunt him when an old adversary returns to the village and with neither prepared to bury the hatchet and move on, his enemy decides to settle their score once and for all. As The Loft blazes, Justin becomes embroiled in the incident and viewers will be left wondering who lives and who dies.
The move comes just three months into Lucy Allan's reign as producer and echoes Bryan Kirkwood's decision to blow up The Dog pub and kill off twin Sophie Burton (Connie Powney) when he took over as the soap's chief in 2006.
Speaking of his decision to leave, Fountain said: "I've been at Hollyoaks for five years now and I've enjoyed exploring and playing the many different sides of Justin. He's been a fantastic character to play and so much has happened to him! I’m actually surprised he’s lasted this long!
"I'll be sad to leave as I've had some great times and gained a lot of good friends at work but I personally feel that it's the right time for me - and Justin - to move on…"
He added: "I've had a great time playing Warren and have thoroughly enjoyed being part of the Hollyoaks cast where I've made some brilliant friends and worked with some great people."
The pair are due to finish filming at the end of the month, while their characters will remain on screen until the final week of May.
Fountain, 21, joined Hollyoaks in 2003 and has been involved in some of the soap's major storylines including Justin's affair with Becca Dean (Ali Bastian), the 'Who Pushed Clare?' saga and baby Charlie's paternity.
Meanwhile, 28-year-old Lomas signed to play Warren in 2006 and quickly became one of the show's central characters during the Kirkwood era, which saw Warren kill Sean Kennedy and frame Jake Dean for the murder, embark on an affair with Mandy Richardson (Sarah Jayne Dunn) and apparently suffocate his fiancée Louise Summers (Roxanne McKee).
Last week, it was announced that Emma Rigby had extended her contract with Hollyoaks by an additional six months, despite originally indicating her intention to leave at the end of this month. She will now continue filming until October.
A source told DS: "Both Emma and Chris were due to leave at the same time, but when Emma decided to stay on until towards the end of the year, producers had to re-work the storylines dramatically."