These are what we call the 'YMMV items.' Things that some people find in this work. We call them 'your mileage might vary' because not everyone sees these things in the same way. This starts discussions in the trope lists, a thing we don't want. Please use the discussion page if you'd like to discuss any of these items.
The black slime golems are worthy runners-up, considering you fight two of them in cramped locales while being blasted by venom crawlers.
Toss all possessor ghosts into the pile: not only do you have to remove them from their human hosts before actually busting them, but they can also turn the other Ghostbusters against you as easily as they do any other human. Expect a lot of running and sliming to keep yourself alive.
There's the Grave Golems that make the Black Slime Golems look like patsies.
Evil Is Sexy: The Spider Witch in the Realistic versions of the game. You wouldn't have guessed from her slashed mouth with fangs, unless you're into that, but in life she was a bizarre yet attractive woman. This was her main way of attracting her victims.
Fetish Fuel: In-story example: If you listen to the messages after the museum level, you'll hear a call from a guy asking the GBs if they'll hook him up with one of the Possessor ghosts you fought.
Goddamned Bats: Has this in the form of flying books that screech like bats. The spider chandeliers qualify too, but they're not nearly as annoying as the bat books who come in much greater numbers. The presence and, in later levels, commonness of "little destroyable ghosts" is a commonly-stated strike against the game.
The Stone Cherubs. DEAR GOD the Stone Cherubs.
Nightmare Fuel: A section of the library full of the ghosts of children. Even Ray is unnerved as you make your way around the room.
Nightmare Retardant: The Juvenile Giant Sloar, when looked at from a certain point of view, is Gypsy on steroids (and possibly roaring drunk, too, what with all the puking it does). Shandor's Destructor form can be seen as this, too: all the potential possibilities, and he limits himself to a stereotype cartoon devil.
Possibly as a result of how stereotypical the devil form is, the "creepy robed man" of the stylized version comes off as legitimately more menacing.
That One Boss: Azetlor. He can move fast, has attacks that can drop you, Egon, and Ray in several hits, has some of the highest health in the game, and can summon Book Bats to help him. You need to move fast and continue reviving your teammates if you intend to survive The Collector.
Uncanny Valley: The realistic version of the game on the PS3 and 360 renders most of the characters fairly close to the way the actors looked in the movies. While it is still somewhat stylized, there are more than a few moments that look almost life-like.
Vigo the Carpathian, the Big Bad of Ghostbusters II, is reduced to nothing more than his painting in the game, unable to do much of anything except talk. To add insult to injury, the painting is owned by the guys who beat him—the Ghostbusters.
The game also made Stay Puft much weaker than before, to the point the player character can take him on. It's actually stated in the game that Gozer's second manifestation as Stay Puft was much weaker than the first.