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The episode begins with the main pups and Spot relaxing on top of a hill. Lucky and Spot are reading Thunderbolt comics, Rolly is snacking (though he becomes interested in what Lucky and Spot are reading), and Cadpig is meditating nearby. She comments on how perfect the day is, and as Lucky says how nothing can ruin it, they hear a loud horn noise.
They investigate to see that Dr. Winokur has arrived in the vet van. Lucky wonders what she's doing there, and Spot figures that since no one is sick or hurt, they're all getting their shots. The pups need to get their shots for "Itchyswellenosis," a disease in which the patient turns pink and green with their noses swelling up and getting itchy. While Rolly looks forward to seeing Dr. Winokur and Cadpig notes that they'll get treats afterwards, Lucky just pictures the entire thing as a Frankenstein-like case, with the needle being fired into him via a canon. He faints as a result.
Cadpig asks if Lucky has shot anxiety, but Spot states that she and Lucky aren't afraid. Lucky faints again, and then so does Spot when Cornelia calls out that it's time for her "chicken pox" shots. Lucky sneaks off trying to hide under the excuse of rounding up the other pups; however, Cadpig isn't convinced by this bluff.
Lucky seeks out various hiding spots on the Dearly Farm, such as the barn, a scarecrow, the mailbox, and even a mine shaft. However, in all of those places, there is always a group of other Dalmatian pups asking him whether he is going to the vet.
Still determined to miss the vet, Lucky hides in the one place where he knows they'll be no puppies: Villa DeVil.
He is able to sneak in via a window, which Cruella opens to shout at an annoying bird. As he sneaks around the Villa, he notices Cruella designing a new dress, using Jasper as a mannequin. Cruella orders Horace to get her pin cushion, to which Lucky notices is right behind him. In shock of being reminded of shots, he jumps from the table he's on, but almost falls on a cactus. He then hides in a yarn bowl and fabrics chest; however Cruella requires both of them, resulting in Lucky being wrapped up on Jasper. The humans fail to notice him, apart from Horace who notices a lump in the dress. Cruella, however, dislikes the dress and orders Jasper to get rid of it. Jasper tosses it (and Lucky) into a chair, before Horace lands on it himself (after being hit on the head by Jasper). Lucky still figures it's better than getting a shot.
Lucky then checks out the window to see if the vet's gone, but sees she's still there. He is then spotted by Scorch, and the ferret chases Lucky through the Villa; however, Scorch loses Lucky's trail when the ferret falls down the laundry chute.
Lucky soon finds his way into Cruella's gym, where he is almost run over by her weights. He then falls into a bucket to see Cruella come in with her trainer for a workout. Cruella, however, skips straight to the rub down.
In the sauna, Lucky is mistaken as a sponge and is used to scrub Cruella's feet, and before he can be used between her toes, Lucky runs back to the farm.
Lucky returns to the Dearly Farm, accepting defeat and saying he'll take the shot, only to learn that the vet is gone. At first, Lucky is glad and figures at least he tried to find her, before Cadpig notices Lucky's spots have turned pink.
Rolly realizes Lucky has gotten "Itchyswellenosis." Lucky's fur turns green and his nose swells up and turns blue. As Lucky itches his nose, Rolly warns everyone to stay back, as the disease is highly contagious.
Fade to Dr. Winokur having vaccinated Cruella, who also has the virus. The show then irises out with Cruella's swollen nose getting caught in it.
- Lucky's nightmare sequence is similar to the 1931 Frankenstein film.
- "Spots and Shots" marks one of the two appearances of the mine shaft near the Dearly Farm; its other appearance was in "The Nose Knows".
- Amongst the many signs outside Villa DeVil are: No Solicitors, No Panhandlers, No Zealots, No Smoking, No Spitting, No White Shoes (after Labor Day), and No Puppies.
- As Scorch falls through the laundry chute, he utters a scream similar to the Goofy holler sound effect in the classic Disney shorts.
- Cruella's gym is also seen in "Cupid Pups", with Cruella also wearing the same clothes she wears there as she does in this episode too.
- This is the fourth time in the series that Lucky's fur is a different color, but it's the second time it's green.
- It is likely that Lucky learned his lesson from "Spots and Shots", since he seems okay with taking his rabies shot in "Spot's Fairy God-Chicken".