Singapore Airlines was the launch customer for the two-deck jet in 2007.
The airline has decided not to renew the A380 plane when the ten-year contract expires next year.
The news comes after Airbus more than halved its delivery target for the A380, raising fears it could slip back to making a loss from the aircraft.
A Singapore Airlines spokesperson said: "Our first five A380s are on 10-year leases, with options to extend. The first expires in October 2017, and we have decided not to extend it.
"For the other four, decisions will be made later."
But they added the airline had orders for five separate A380s with Airbus, which will start being delivered in the second half of 2017.
The A380 only began breaking even for Airbus last year.
In July, Airbus said it would still avoid losing money on the jet in 2017 with as few as 20 deliveries, but gave no further guidance.
Analysts say that big aircraft like the A380 and Boeing's 747 series have fallen out of favour.
Smaller jets can be more profitable as they are easier to fill and are cheaper to operate, analysts say.
Singapore Airlines has decided not to keep the first A380 it leased, delivering a fresh setback for Airbus' super-jumbo plane.