Iberia has cancelled more than 400 flights out of 1,000 scheduled for this week, with cabin crew and baggage handlers staging the walk-out.
A lack of services at Spanish airports are expected to affect more than 1,000 flights from various airlines.
Iberia has announced plans to cut 3,807 jobs after it reported mounting losses last year.
In the first nine month of 2012 it lost 262 million euros ($349 million).
Unions are planning three separate five-day strikes in February and March.
Iberia said 70,000 passengers would be affected by the first strike, though in a statement the company said 60,000 had been found seats on alternative flights.
It said 90% of long-haul flights would be operating, but domestic flights would be the worst affected, with more than half of flights grounded.
Analysts suggest 15 days of strikes could cost Iberia up to 100 million euros.
Iberia merged with British Airways in 2011 to create International Airlines Group, and the new management has been trying to cut costs.
Iberia has been hit by increased competition from low-cost carriers and a prolonged recession in its home market.
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