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Should I say:

  1. I've made a huge mistake by accepting this offer
  2. I've made a huge mistake in accepting this offer
1

I have made a huge mistake by accepting this offer.

I have made a huge mistake in accepting this offer.

I think there's no difference in meaning between these sentences.

You usually use the structure mistake + in + -ing form. Even you can drop the preposition 'in' that's optional.

I have made a huge mistake accepting this offer.

It'll also be grammatical if you say:

I made the huge mistake of accepting this offer.

As for the use of the preposition "by", though not as common as in, it's also correct in the sentence; we use it for stating the way we do something.

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0

Both of these choices are perfectly correct. It is immaterial whether you choose by or in here, since the meaning really does change depending on your choice.

I suppose you could argue that the first choice "by" has a nuanced and very slight implication of a more passive acceptance, and the "in" has a nuanced and very slight implication of a more active acceptance, but, that arguement is really splitting hairs.

The choice between by and in here is entirely a personal choice based on the sound of the sentence, and not its meaning. I hear both usages on a regular basis in my everyday life.

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