There's a wide price variation and the WSJ's Scott McCartney says that none of the sites is consistently cheaper than the others. So it pays to shop around. To give you some idea of the mind-boggling mathematics involved, a trip from JFK to LAX can have over a billion possibilities.
At the root of the fare tangle is the complexity of airline pricing. Airlines file prices for every conceivable route they can offer with their schedule, plus flights offered by their partners, to a company called Airline Tariff Publishing Co., which is jointly owned by 17 airlines and distributes data several times a day to reservation systems. Each route may have 20 different prices from each airline, and 50 to 60 different rules--certain fares may be used only on Tuesdays, others must be sold 21 days before departure, some only apply if you connect in Chicago, for example. As well, the inventory of fares on a flight changes constantly.
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Overall, what helps differentiate each site are handy tools that can make shopping easier. Microsoft Corp.'s Bing, for example, provides fare history--you can see what the price for a trip was over the past five months for a read on how high or low it might go. Hipmunk displays flight options in colored time bars making it easy to see connections and what time of day flights depart and arrive. You can sort by Hipmunk's "agony" index, a combination of price, duration and number of stops.
Anyone over 40 might recall that before deregulation the carriers were required to file specific pricing schedules with the Civil Aeronautics Board. Anytime they wanted to add or subtract they had to go back to the government. The current system is a mess in many ways, but at least it offers multiple options, as well as speed.