Under a tax scheme in place since 2005, some firms could reduce taxable profits in Belgium by up to 90%.
Companies that were not part of global groups could not claim the same benefits, which Europe's Competition Commission said "distorts competition".
European firms were the main beneficiaries, according to the EU.
Commissioner Margrethe Vestager, in charge of competition policy, said: "Belgium has given a select number of multinationals substantial tax advantages that break EU state aid rules. It distorts competition on the merits by putting smaller competitors who are not multinational on an unequal footing.
The so-called excess profit scheme has been on hold since 2015, when the EU announced its investigation.
The Commission did not mention any firms by name, but media reports said they included brewer AB Inbev and British American Tobacco.
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