Ryanair says it will cancel 150 flights out of 400 scheduled to fly to and from Germany on Wednesday due to a 24-hour strike by pilots and cabin crew.
The row over pay and conditions follows a series of strikes over the summer, with walkouts in Germany, Sweden, Ireland, Belgium and the Netherlands.
Affected passengers would be offered alternative flights, the airline said.
In August, Ryanair struck a deal with Irish pilots and said it was hopeful it would secure further deals.
However, since then seven trade unions representing cabin crew in Italy, Portugal, Belgium, Spain and the Netherlands have threatened to strike later this month unless the airline improves working conditions.
The unions have warned it would be "the biggest strike action the company has ever seen".
The Irish airline, Europe's largest low-cost carrier, said Wednesday's strikes would "damage Ryanair's business in Germany" and described them as "unnecessary".
"These are wildcat strikes designed to cause maximum disruption to our customers and maximum damage to the Ryanair business," said Ryanair's chief marketing officer Kenny Jacobs, speaking at a news conference in Frankfurt in Germany.
The Vereinigung Cockpit pilot union and the Verdi services sector union say there has been no progress on their demands, despite repeated negotiations with management.
But Ryanair argued it had offered more local contracts and pay rises for pilots in Germany.
"It is unacceptable that a union representing Ryanair's German pilots, who earn up to €190,000 a year and work a five-day week followed by a four-day weekend, is now threatening customers' travel plans at short notice," Mr Jacobs added.
Ryanair agreed last year to recognise unions as official representatives for workers for the first time in its 33-year history.
The move followed a scheduling crisis last September which led to the cancellation of thousands of flights.
So far the airline has agreed a deal with Italian pilots over working conditions and last month, Irish pilots voted to accept an agreement on improved working conditions.