A 300th episode is a milestone extremely few series get to celebrate.

Maybe that doesn’t seem as surprising for a drama that has spent much of its run heralded as “the most popular show in the world,” but it’s a major moment for “CSI: Crime Scene Investigation” nevertheless.

The globally successful Anthony E. Zuiker-created procedural — which inspired much of what CBS’ prime-time schedule has looked like for the past decade-plus — marks the event Wednesday with a story that acknowledges “CSI” history in a number of ways. The plot revisits a cold case from the Las Vegas forensics team’s early days, and founding co-star Marg Helgenberger (who will be back on CBS weekly this winter in “Intelligence”) returns as Catherine Willows.

Paul Guilfoyle, alias Capt. Jim Brass, has been with “CSI” from the start. “It’s kind of an abstract number,” the actor reasons of reaching the 300th tale. “It’s almost like waking up and looking in the mirror. You know time is going by. Having been in 150 different productions, this is my first television show as a regular ‘regular,’ so I never expected to have such a long-distance run.

“It’s kind of like the work my father did, having a craft and participating in manufacturing something every day. It feels old-fashioned in a way, and there are a lot of good things about it. There are 250 workers in this production, many of them behind the scenes, and I’ve learned to become one of them.”

Now in his third of the 14 “CSI” seasons, Emmy winner and television staple Ted Danson — who plays ever-pensive team leader D.B. Russell — first worked with Guilfoyle in the hit 1987 movie comedy “Three Men and a Baby.” He allows he’s one of the relative new kids on the “CSI” block, but he knows from his long runs on the sitcoms “Cheers” and “Becker” the significance of episode No. 300.

“I feel very clever that I joined the show when I did, so I can pretend I had something to do with this,” Danson muses. “They had a cake for the crew and everybody, and (executive producer) Jerry Bruckheimer and all the CBS executives who have been part of it were all there … and it was so sweet to look around and realize there were cast and crew members who had been there from day one.

“Besides being really good at what it does, that tells you that the people who created this did something quite amazing. They created something long-living that people want to show up and go to work for every day. Including me.”

Danson appreciates that the 300th episode, also featuring Bethany Joy Lenz (“One Tree Hill”) and Jason Priestley as guests, “really honors those characters who have been there from the start. It takes them back to the first year of the show, and they do this great thing called ‘faux-backs,’ instead of flashbacks. They use the actors as they are today, and Marg came in and shot some — which tells you how remarkable she is, to still look like she did 12 years ago.”

As Helgenberger’s Catherine ended her weekly “CSI” run, Danson’s Russell saved her life by racing to her rescue, but he reports that filming didn’t go entirely as planned.

“She came sprinting down this long driveway in high heels, ducking bullets, and I came roaring up in my SUV and slammed the brakes and yelled, ‘Get in!’ She was supposed to open the door and dive in, but if you don’t stick the car in park, all the doors lock automatically. And she had to do the whole take over because she couldn’t get the back door open. She wasn’t totally fond of me that evening.”

Also a familiar face from numerous other movies, ranging from “Wall Street” and “Air Force One” to “Primary Colors” and “Quiz Show,” Guilfoyle is pleased he’s still getting new chapters of Brass’ story. A big one launched the current “CSI” round, when the cop found his ex-wife killed by the deeply embittered Ellie (Teal Redmann), who had learned she wasn’t his biological daughter.

“When this first started in 2000, and it achieved some success, it was funny to watch everybody run to the front of the line and take credit,” Guilfoyle recalls of the series that ABC originally passed on. “And I mean everybody, from the craft-service guys to entertainment lawyers throughout Hollywood: ‘I put the deal together! I did the deal!’ They all wanted to be part of it, but it was so successful, it frankly overwhelmed anybody’s individual participation.

“The only thing I can think is that it struck some kind of psychic chord. It hit something where people wanted this kind of answer to metaphysical problems; they wanted technology to provide the way to stop the lies that were showing up in our culture, and this particular show presented true evidence so people couldn’t get away with stuff anymore. It was a place where truth could live, and I think the audience saw that and invested in it.”