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The original Little Orphan Annie comics feature horrific, pure white eyes utterly empty of soul or emotion, on every character, for no apparent reason.
In 1970s Marvel Comics, this was Spider-Woman's shtick; her comic's tagline was "To Know Her Is to Fear Her!" She is, biologically, literally part spider, and was raised by Petting Zoo People and Beast Men to boot. When she finally enters the human world, nearly everyone is instantly, instinctively afraid of her, making it extremely hard for her to find work or shelter, and leaving her terribly alone. Still, through tremendous effort, she eventually overcomes this and makes a good life for herself, making for a very inspiring character arc. However, Executive Meddling later put her on a bus for 20 years, and when she was finally brought back into the limelight, this whole aspect of her origin was retconned away.
Meanwhile, Spider-Man also hits this trope, which is why he's a case of Creepy Good; the costume is just startling, even compared to other super-heroes', since it basically gives him a round, blank face that's featureless save for two huge, white, ever-staring eyes. The garish red and blue costume is creepy enough, even despite the bright colors (or perhaps because of them, since brightly colored, in nature, typically means "Danger! Poison!"), but when he wears some of his darker costumes, like the black-and-white one that eventually became The Symbiote, it's only heightened. To this unsettling appearance is added his inhuman flexibility; if you look closer, you'll see a lot of the poses that Spidey so casually strikes are extremely awkward, if not impossible, for an ordinary human to achieve, which further makes him look like a monster. Add to this the Paranoia Fuel his Wall Crawling abilities give him (meaning, he can come at you from anywhere, at any angle), and it's surprising just how spooky he is.
Scott McCloud's Making Comics had a few pages of faces showing various basic facial expressions as a guide to how that kind of thing works. And as McCloud himself admitted, they were creepy as hell.
His drawn face with big blank glasses could sometimes look fairly soulless.
The "photorealistic" painted style of Kingdom Come and Marvels falls into this sometimes, more so with the latter.
The New 52 Joker takes the cake, since he had his own face sliced off and wears it like a mask, often using it to make himself even more unsettling.
Fall of Cthulhu introduced a brand new character to Lovecraft's mythos: The Harlot, a keeper of all men's secrets, whose giant green head houses a nose too flat and a pair of juicy red lips a little too big. She's a wonderful example of what a Humanoid Abomination would look if it took up burlesque fashion.
Beautie from Astro City fits this trope; she is a living, life-sized Barbie doll, so it makes sense.
She's also painfully aware of it, and deeply disturbed when men find her attractive.
The caricatures from the 19th-century political satire magazine Puck can come across as this, on account of the photo-realistic style.
This happens whenever Gary Larson tries to emulate the style of more serious cartoons (to parody them, usually) that they get creepy.
Quite a few mainstream comic publishers have been using Poser for some of their comics. It always looks terrible.
As good as Sara Pichelli's work in Ultimate Spider-Man is, the artwork can sometimes fall into this with the extreme detail of the facial expressions.
Alex Ross' art tends to invoke this, due to how ridiculously detailed he makes his characters.
The National Lampoon ran an article showcasing the 'real' people who were inspirations for newspaper comics - featuring lovingly rendered, realistic pictures of the subjects who were dead ringers for the likes of Dick Tracy, Little Orphan Annie, Popeye, and the Nightmare Fuel that was Henry.