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I was used to use "What are the difference between _____ and _____", but when I accidentally typed "What is" on English StackExchange asking question, it shows up "What is the difference between _____ and _____" too!

Then, I became bewildered which word is most appropriate in the situation that I do not know whether there will be multiple differences or only one.

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Both "What is the difference between X and Y?" and "What are the differences between X and Y?" are grammatical and will be understood.

According to my native-speaker intuition, "What is the difference ...?" is the normal phrasing. I would only use "What are the differences ...?" if I was already pretty sure that there was more than one difference.

EDIT: Some additional cases that came up in the comments:

  • The labels "X" and "Y" will, of course, always be different, but that does not count as a difference between the things X and Y, and therefore is not a reason to use the plural form. The answer to "What is/are the difference/s between ice cream and ice-cream?" would be "There is none, they are the same thing."1

  • "What is a difference between X and Y?" is also grammatical, but it means something that one hardly ever wants to say: the speaker has deliberately refused to indicate how many differences he or she thinks there are, and no matter how many the listener thinks there are, the speaker only wants to hear about one of them. The only time I personally would use this variation is if I was writing an exam question.

  • "How do X and Y differ?" is an alternative phrasing that avoids the question of number altogether; unlike "What is a difference...", it carries no special connotations.

1 Consider also tomAYto versus tomAHto. You might find it helpful to read up on the use-mention distinction.

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    "What is a difference" is grammatical, yes, but it's almost never what you want to say. It means: you are refusing to indicate how many differences you think there are, and regardless of how many there really are, you only want to be told about one of them, respondent's choice. The only situation I can think of, right now, where this would be the desired form is if you're writing exam questions.
    – zwol
    Apr 24, 2015 at 18:49
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    (I should probably add: Native speakers of English know very well that the choice among a, the, and no article is one of the hardest aspects of the language for non-native speakers to get 100%, and will cut you lots of slack.)
    – zwol
    Apr 24, 2015 at 18:56
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    But if you wanted to leave number totally unspecified you might ask, "How do X and Y differ?"
    – Jim
    Apr 25, 2015 at 3:57
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    @XPMai Unrelatedly, FYI, AmEng requires one to say "you could reply that ..." with no "me" in there. (I can say "reply to me" but not with a "that"-clause following.)
    – zwol
    Apr 26, 2015 at 1:39
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    @XPMai You should just say "you could reply that ...". No to, no me.
    – zwol
    Apr 26, 2015 at 16:23

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