The United Auto Workers (UAW) union has expanded its ongoing strike by shutting down Ford's biggest plant.
The UAW said 8,700 workers walked out of the truck plant in Kentucky, in response to Ford refusing to move further in contract bargaining.
It is a sharp escalation of its strike against Ford, General Motors and Stellantis, which began last month.
The UAW is pressuring the carmakers to grant higher pay and make other improvements in new labour agreements.
It is the first strike in the union's 88-year history to target the Detroit Three automakers, which collectively employ more than 140,000 UAW members, at the same time.
With Wednesday's walkout, which has halted production of lucrative pickup trucks, about a fifth of the auto workers have now downed tools.
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In a statement, Ford called the latest move by the UAW "grossly irresponsible".
Ford's Kentucky truck plant generates $25bn (拢20b) in annual revenue, accounting for a sixth of the company's global car revenue.
The latest walkout is a warning to General Motors and Stellantis, where negotiations with the UAW are ongoing.
It also comes at a time of broader labour unrest and casts a cloud of uncertainty over an industry that accounts for 3% of the national economy.
Two weeks ago, US President Joe Biden became the first sitting US president to visit their picket line to back striking cars workers in Michigan, where he said the workers "deserve" raises and other concessions they are seeking.
