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Is it better to say "what's wrong with something" or "what's wrong in something"?

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The choice of prepositions for this kind of expression is really arbitrary and sometimes varies by region. Most people are used to the expression "wrong with" meaning a defect, whereas wrong meaning incorrect might take "in." For example, the use of the Cyrillic alphabet would be wrong in this context.

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"the use of the Cyrillic alphabet would be wrong in this context" is not an appropriate example, as "in" is part of "this context", not part of "wrong". For example, you could equally say, "the use of the Cyrillic alphabet would be wrong here". – Steve Melnikoff Aug 26 '10 at 12:12
@Steve Melnikoff: But doesn't the same apply to the example at hand? It's perfectly valid to say "in this sentence" to specify the location where you're looking for something wrong. Consider the difference between "Something's wrong with my house" (it has no roof), and "Something's wrong in my house" (the cooker is on fire) - the meaning is different, but both are perfectly valid. – psmears Jan 18 '11 at 19:36
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Without knowing the context, "what's wrong with something" is correct. The question "What's wrong in something" sounds like a question you would hear in a philosophy class on existentialism.

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what's rotten in Denmark? – Joel Spolsky♦ Sep 9 '10 at 18:15
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Perhaps it's just my own idiolect, but to me "What's wrong in something" implies that the speaker refers to a collection of things, one of which is presumably wrong. "In" denotes that the item in question is in some way contained.

"What's wrong with something" may be used for a group, but may also be used for an individual item—"What's wrong with Paul?"

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