In On Writing Stephen King says:
A strong enough situation renders the whole question of plot moot, which is fine with me. The most interesting situations can usually be expressed as a What-if question.
In all honesty I don't see much difference in "plot" and "situation", but let's talk about using What If as a starting point for a story. Sometimes a novel will start with a character that is so compelling, he won't stop haunting you until you tell his story. Sometimes a novel will start with a question. What if this happened, what if that happened? That initial question will invariably lead to more questions. For instance, what was the fallout? Who was affected? How did they react? All of these questions are just a variation on the theme of, and then what happened? What if is your jumping off point, and if it's compelling enough you'll jump into the story with or without a safety net.
For Bring On The Night my initial question was, what if the noir tough guy was both a girl and a vampire? Followed by the question, what if she didn't brood and fall in lurve? I went from there, asking more what ifs as the story progressed. With the short story that eventually mutated several times until it became Mojo Queen, my starting point was, what if someone chose to be possessed by an evil spirit? Mojo Queen went through quite a few incarnations but in the end that initial question could still be found as an integral part of the plot. I found myself floundering when I tried to write a follow-up, until a question occurred to me: what if a natural disaster, like a flood, created havoc on the spirit plane just like those events do in the physical world? How would ghosts and spirits react, how would that affect people, and what would it take to calm these rattled spirits down again? I've worked out answers to the first two of those questions and I’m sure I'll figure out the third one in the course of writing. I’m also sure more questions will come up.
Have you ever started a story with a what if question? Was that a successful way for you to start?