For any airliner, the cost per seat mile (or kilometer) is a key metric. Jumbo jets like the 747 and A380 can have very low per seat costs, especially on long flights, but that depends on the passenger load. They consume a huge amount of fuel during takeoff and climb to altitude, but then are very economical during cruise.

There are many factors that dictate the operating cost for a plane. There is acquisition cost and amortization over the plane's operational life (as much as 30 years for the 747). There are maintenance costs (very well known for the 747, largely unknown for the A380). There are fuel costs*, crew costs, and insurance. None of these things will be cheap for a plane like the A380, where a catestrophic accident could result in a couple billion dollars in lawsuits.

Factoring in all of that, it takes a certain percentage of butts in seats for any flight to break even**. There's a reason why smaller airliners like the 737 and mid-sized airliners like the A320 and 767 have sold so well - they're easier to fill and be profitable. They're also much more flexible than the jumbos.

The A380 is a very large plane that's most efficient on long flights (remember all that fuel burned for takeoff and climb). For most airline routes, there are peak seasons and then slow times. During the peak seasons, it's relatively easy to fill jumbos. During the slow times, smaller planes are often used. The jumbos are switched over to service other markets during their peak seasons. As an alternative, some are looking into converting the jumbos into freighters or combos (passengers and freight) to keep the utilization and profitability high.

Currently, there aren't many airports that can handle the A380 without expensive modifications. Will there be enough mission flexibility to keep the planes profitably employed year round? Time will tell - they said similar things about the 747 when it entered service. There are also ground logistics considerations, such as the ability to handle so many passengers and all of their baggage. Jumbos tend to put a real strain on the system, especially for people with connecting flights. If I were riding on an A380, I'd probably want at least an hour before a connecting flight to hope my baggage gets to the right plane and me, too. It'll probably take a long time to load and unload all of those passengers.

*I read an article recently that said that the new generation 737-800 airliner is very fuel efficient on long routes. You can load well over 100 passengers and fly them from New York to California with an average per passenger fuel consumption of about 35 gallons. That's far less fuel than it'd take to drive the distance, even in a hybrid car. The 7E7 is designed to be at least 20% more efficient than existing airliners while offering the flexibility to serve a wide variety of markets. It could well be a very successful design.

**This is why those small regional jets have proven so popular with the airlines. It's much easier to fill an RJ to the break-even point than a 737 or MD-8X airliner, making them more profitable especially when servicing smaller markets. If it wasn't for RJ service, we probably wouldn't have half the number of daily flights to and from Colorado Springs.