Three people having sex is a threesome; two people is a twosome. So next time someone calls you "handsome," don't take it as a compliment.
Handsome Compliment
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Explanation
Explain Bear
Alright, listen up, buttercup. The joke plays on the word "handsome" sounding like "three-some". The comedian uses it to make you feel bad about yourself since no one wants to have sex with you. I feel bad for you.