A "major incident" at the Holby hospital sees various characters from Holby City interacting with those in HolbyBlue when they attend the police station to be interviewed.
The show's creator Tony Jordan told Digital Spy: "There are several familiar faces from Holby City appearing in the first episode of HolbyBlue in a dramatic and intriguing storyline that spans both shows.
"I don't want to give too much away at this stage but suffice to say the arrest causes a stir at Holby City General and the officers at Holby South Station have their work cut out for them as they have conflicting witness statements and very little evidence to go on.
"The case tests the skills of CID especially John Keenan and Luke French who are pushed to the limits.”
John Yorke – the BBC's Controller of Continuing Drama Series told The Stage: "Loads of questions are asked in the Holby City episode that are answered in the HolbyBlue episode.
He added: "It is something the Americans have done for years with shows like CSI and I really like it. You really believe it's a world."
It isn't the first time another show's character has appeared in HolbyBlue. The first episode of the show's debut run saw Derek Thompson – who plays Casualty veteran Charlie Fairhead – help lead HolbyBlue character DI John Keenan's (Cal Macaninch) daughter who had her finger stuck in a bowling ball.
The special crossover episode has been written by former EastEnders writing duo Tony McHale and Tony Jordan.
HolbyBlue was re-commissioned in June for a second, extended run of 12 episodes.