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It varies person to person. I have had no trouble with it after many hours of playing, but a few people get headaches. Try it out for yourself, and make sure you try adjusting the 3D slider if it isn't comfortable at first - don't just keep it all the way up all the time!
If a person has been playing a video game such as 3D Nintendo for a long period of time, they can get a headache and their head will hurt. This can usually be the result of fatigue in the eyes and neck.
No, most people don't experience migraines for playing over 15 minutes on the 3DS, although it is possible.