Cuddles and Toothy have been seen together many times throughout the show. As the show's protagonists, they are the most common paring in the entire series. It has been shown that they are best friends, and any conflict is extremely rare.
Similar to Giggles and Petunia, it is implied that Cuddles is Toothy’s best friend and they are often seen doing activities together though almost always with at least one other character. In Spin Fun Knowin' Ya and Blast from the Past, they play at the park together with Lumpy and Giggles; in Class Act, they acted in a school play together along with Giggles, Sniffles, and Nutty; in Remains to be Seen, they went trick-or-treating with many other characters; in From A to Zoo, they went on Lumpy’s school field trip along with several other characters; in Take a Hike, they went on a camping trip with the same group of characters with the addition of Nutty; in Snow Place to Go, they went on a sailing trip with several other characters; in Party Animal, they attended Flippy’s birthday party; in Concrete Solution, appear sitting together at the cafe, seemingly having a friendly chat using their eyes given how often they glance at each other; in Autopsy Turvy (Double Whammy Part II), they play dress-up together with Cro-Marmot; in Can't Stop Coffin, they played baseball with Russell and Cro-Marmot; in Wrath of Con, they walk together into the convention center, and later attend Splendid's speech; in Strain Kringle, they play with snowballs, with the former looking for unsuspecting targets; in Who's to Flame? and Mime to Five they are even co-workers and seem to work well together; and in Going Out With a Bang, they light fireworks together. Toothy often seems quick to follow along with Cuddles’ naturally mischievous behavior when he is not known to do so when he’s alone. In From A to Zoo, he teases a baboon and even let’s himself be used for Cuddles to stand on so he can terrorize a rhinoceros through a small hole and in Strain Kringle, he followed Cuddles’ instructions to throw a snowball at Lumpy. He is also quick to make up with Cuddles at the end of Camp Pokeneyeout.
There is only one example against Toothy’s opinion but nonetheless, the conflict was very major and very famous as in Camp Pokeneyeout, a misunderstanding on Cuddles’ part leads to a full on physical battle with slingshots that many other characters got involved with though Toothy himself with very quick to retaliate and allow the situation to escalate.
Likewise, Cuddles considers Toothy to be a great friend. In Take a Hike, he watches over Toothy while Lumpy sucks the venom out of Toothy’s arm. Though, while this appears to most likely have been out of concern, there is a distinct possibility that this was at least partially out of curiosity. Similarly, in Snow Place to Go, when Toothy’s nerves freeze on the snow burger, Cuddles is shocked and later saddened by his friend’s injuries. At the beginning of Blast from the Past, he and Giggles both tried to comfort Toothy after he breaks his arm. Cuddles even managed to successfully save Toothy from injury in Autopsy Turvy by catching Toothy when he tripped and was almost impaled in the eye by a coat rack.
Cuddles’ side is however much less clean cut than Toothy’s, though not nearly as much as to Flaky, Cuddles’ mischievous behavior can sometimes be turned against Toothy. Starting back at the famous slingshot battle in Camp Pokeneyeout, Cuddles was the one to start it, when an acorn falls out of a tree on to Cuddles’ head, he very quickly and falsely assumes that Toothy had fired it at him from the slingshot Toothy was using to practice his aim by shooting at cans. Because of this assumption, Cuddles pulls out his own slingshot and opens fire. As a less famous example, in From A to Zoo, Cuddles chooses to stand on Toothy’s back in order to have access to the rhino even though, later in the same episode, Lumpy easily reaches a nearby crate to put Toothy on that Cuddles could have very easily moved over and stood on instead. Also, when Lumpy found them and rushed over, Cuddles immediately ran over leaving Toothy to possibly get punished for what they were doing. In We're Scrooged, he plays with Toothy's severed finger and shows no concern about the fact that his best friends' finger flew near him. A final, very little known case is that, if one pays close attention, when Toothy is first bitten in Take a Hike, Cuddles can be seen running off to an unknown location, though he had obviously returned, he was running in the opposite direction he would need to go to get help so it is most likely that he was running to avoid being bitten himself, which is ironic because Cuddles is best known for his bravery.
- They, along with Giggles and Lumpy, make up the four primary characters of Happy Tree Friends.
- They are each others most frequent victims.
- They are Lumpy's most frequent victims.