Spot the Signs. Do you have a good relationship with your manager? Is he or she relatively reasonable? Do you have regular one_on_ones where you talk about your career goals and growth? If so, it's likely that your boss will accept your resignation with grace, help develop a plan of action for your last two weeks, and maybe even attend your farewell happy hour.
Sure, it may sit in the depths of HR until the end of time, but you can be sure of two things: One, your former boss (and future reference) will read it and be impressed. And two, if you ever decide to come back to your company (hey, it happens), it's a very good thing that last thing on file is a great, professionally written resignation letter.