Is there a difference between saying What's the problem with you? and What's the matter with you?
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As always, the answer depends on the context. In some cases, they may be interchangeable, but there's at least one instance in which they are not. What's the problem with you? is invariably critical, but What's the matter with you? may be used as a neutral inquiry about someone's medical condition.
I don't hear regular English speakers say "What's the problem with you?" It's "What's wrong?", "What's the problem?", "What's the matter?" none of which are necessarily critical. You can add "with you" to the first and last, which could sound critical, depending on the context, but saying "What's the problem with you?" doesn't sound like regular English to me.