But any hopes viewers had of the will-they-won't-they pair finally getting together were scuppered by the departure of Tom Ward who, after a decade as pathologist Harry, called time on the show at the end of the last series.
So as the drama enters its 16th season, there's a new man on the scene to help fill the void at the Lyell Centre. In an effort to keep his investigative team up to date, Professor Leo Dalton, played by William Gaminara, brings strapping young forensic scientist Jack Hodgson (David Caves) into the fold.
For Emilia Fox, who has played Nikki since 2004, Ward's exit was "really sad, of course", but not a huge surprise after such a long stint on the show.
Her alter ego, however, is experiencing "quite a lot of denial" since Harry left to take up a post in New York.
"There have always been feelings there, which is why there are feelings that he's gone," the actress explains. "And yet it's a really hard thing to do because it could slightly overwhelm the series that Harry and Nikki are not together again.
"So this series is more about re-forming relationships and also letting David come in and take his place in the trio. What's also good is that his is a different job from Harry's so there's no suggestion of replacing him. It's a completely new energy and skill coming in."
Viewers first meet Jack when he shows up to hunt for clues in a hotel room, the scene of the mysterious death of the wealthy boss of a sweets firm.
Caves describes his character, a cage-fighter in his spare time, as "a bit of a maverick".
"He's loose around the edges at times, but very good at what he does. He's very focused and driven and wants to make an impression as he has come to work for these guys."
The nature of his job means he takes a different approach to investigations to his colleagues ("I'm more involved in taking evidence from the actual crime scene itself, and these guys are more focused on the body"), making situations ripe for disagreements.
"Most of the time I come up with some sort of crazy idea about something without that much evidence to back it up at that point. I put it out there and it's ridiculed by the pros here," he says, laughing.
Though he is an accomplished stage actor, Silent Witness is the first TV role for Caves, and he admits he was "like Alice in Wonderland" when he first arrived on the west London set.
"I just couldn't believe I was there. I did a little dance to christen the cutting room."
As well as dealing with a lead part in such a popular series, he has had to get to grips with all the dead bodies on the show, recreated on screen by a mix of prosthetics and carefully made-up actors lying on the slab.
"It's amazing how quickly you get used to it, actually. What the art department and props do with those bodies is incredible."
So will there be any chemistry between Jack and Nikki?
"Certainly from Jack's point of view there is," says the actor, who is from Belfast. "With any female in the vicinity, there's a guaranteed flirtation. But yeah, we do have a bit of banter."
However, Nikki gets her own romantic encounter this series, with a science minister played by Fox's Upstairs, Downstairs co-star Ed Stoppard.
"I get taken out on a date, eight years in!" the actress declares triumphantly.
"It's nice. You get to see Nikki having fun this series."
Indeed, Fox admits she frequently begs the writers to allow her character to loosen up.
But she is at pains to point out that the team behind Silent Witness are conscious of how dark the subject matter can be.
"This series is very much about diluting it and focusing a bit more on the part forensics play and on the relationships between us slightly lifting it out of that darkness.
"It's a very difficult thing because it's often violent death we're dealing with ... and getting the balance right is something that we're all aware of."
Despite the elaborate plots, the show is sometimes eerily close to life. Last season, a two-parter had to be postponed because of similarities to a real-life child sex grooming case.
The show also hit headlines in April after hundreds of viewers complained to the BBC following scenes depicting the aftermath of a savage beating.
The actors say the show means they take a keen interest in real news events.
Referring to the case of Ian Tomlinson, who died during the G20 protests, Gaminara says: "The pathologist there has been struck off now. And that just resonates a bit more now.
"Sometimes our characters disagree about things but in real life that happens and it has real consequences."
Gaminara has been with the show since 2002. So what does he think is the secret of its success?
"The thing that really pulls people in is the idea of a body giving up secrets. And however much you modernise it, bring in new characters and new technology, as long as that idea is at the heart of it, people are interested."
l Silent Witness returns to BBC 1 tonight at 9pm.