Budget airline bmibaby is to halt its operations from Cardiff Airport from this autumn.
The firm, which employs 69 at Cardiff, blamed the economic climate, saying it would focus on airports with strong growth opportunities.
It said it would be redeploying aircraft to Northern Ireland and the Midlands.
Cardiff Airport said it was "disappointed albeit unsurprised" at the news.
The airline, which is also withdrawing from Manchester, started operating out of Cardiff in winter 2002.
It started with 12 destinations and more than 100 flights a week to UK and European destinations from the city, having first launched at East Midlands airport earlier that year.
The airline said it currently operates nine routes from Cardiff - to Geneva, Faro, Belfast City, Malaga, Murcia, Alicante, Ibiza, Palma and Mahon.
A bmibaby spokesperson said: "In the current economic climate it is essential for bmibaby to focus on airports where the airline already has a strong market presence and where there are strong growth opportunities for the bmibaby business."
The company said it would transfer two Boeing 737 aircraft currently based at Cardiff, and two more based at Manchester, to Belfast, Birmingham and East Midlands airports.
The spokesman added: "bmibaby will therefore cease operations from Cardiff Airport and from Manchester Airport from the end of the summer 2011 flying schedule.
The firm said it would be entering into a minimum 30-day consultation process with all of the respective unions.
Cabin crew and pilots based at Cardiff and Manchester would be offered the chance to redeploy to the Midlands.
The airline said its 69 staff working for bmibaby at Cardiff Airport had been told on Wednesday they are at risk of redundancy.
Some 44 cabin crew, 24 pilots and one manager had been given 30-day redundancy notices.
However, the company said it had enough similar positions at East Midlands and Birmingham Airports for them all to directly transfer to if staff decide they want to.
The airline has announced seven new routes from George Best Belfast City Airport.
Flights to Malaga, Alicante, Palma, Faro and Ibiza will run from March 2012, and go on sale on Wednesday.
A year-round service to Amsterdam will also operate from October 2011, along with winter flights to Geneva for 2011.
In a statement Cardiff Airport said: "Cardiff Airport is disappointed albeit unsurprised at bmibaby's decision to withdraw from Wales altogether."
The statement said that since 2006/7 when bmibaby accounted for 34% of passenger volumes there that had declined to less than 14% in 2011, having a huge impact on overall passenger statistics.
'Sun and the sand'
It continued: "Since 2002 both Cardiff Airport and the Welsh Assembly Government has provided significant support for bmibaby to operate in Wales, as the nation's low cost carrier, only to see this announcement appearing today.
"It is regrettable that bmibaby has cited the economic climate as its reasons for withdrawing both in Manchester and Cardiff as both regions have demonstrated strong economic prospects."
Airport managing director Patrick Duffy said: "It's not a question of saying no to Wales, it's a question of consolidating their fleet... which is getting smaller and smaller every year anyway.
"This has been predictable for three or four years and in that time we have been contemplating what life would be like without them.
"The sun and the sand is still available - there aren't many routes that weren't covered by somebody other than bmibaby so it's not as if there's going to be an inability to get somewhere."
The airport said last month had seen the start of the Helvetic Airways 4 weekly service to Zurich achieved through a joint partnership approach.
It said it looked forward to working with other airlines and other partners "to facilitate increased opportunities going forward".