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There were two Unions of Brussels, both formed in the end of the 1570s, in the opening stages of the Eighty Years' War, the war of secession from Spanish control, which lasted from 1568 to 1648. Brussels was at that time the capital of the Spanish Netherlands.

A part of the Netherlands, the counties of Holland and Zeeland rebelled in 1572, when Calvinists took over control of most of the cities. The Spanish army tried to reconquer them but failed during the Siege of Leiden in 1574. The Spanish treasury was empty and the Spanish soldiers mutinied, pillaging the countryside of Brabant and Flanders and the city of Antwerp, where 10,000 inhabitants in a city with 100,000 people were killed by the Spanish soldiers, who tried to kill all the local Protestants.

This event discredited the Spanish army enormously. The Estates-General of the Netherlands, sitting in Brussels, wanted to make an end to the warfare in 1577. A problem was that some of the fervently Roman Catholic provincial Estates didn't want to invite the Calvinists of Holland and Zeeland to join. The Estates-General, without Holland and Zeeland, founded the first Union of Brussels. King Phillip II of Spain agreed with this.

The leader of the resistance, Prince William of Orange, went to Brussels in 1577 to try to convince the General Estates to accept the Calvinist provincial Estates of Holland and Zeeland. The population of Brussels celebrated him as a hero, and the General Estates accepted Holland and Zeeland. Lots of turmoil broke out in the Netherlands when the news spread throughout the realm. Calvinists took over the cities in Flanders and in other provinces of the Netherlands. The Estates of the eastern provinces didn't accept this. The French speaking provinces in the south started the Union of Arras in 1579, when the French-speaking Protestants were driven out. The Stadtholder of Groningen and Drenthe supported the king, and the city of Amsterdam as well. The Calvinists had taken over most of the Netherlands and they created the calvinist Union of Utrecht the same year. The Union of Brussels came to an end. Most of Brabant including the city of Brussels were neutral. The General Estates, which were dominated by Calvinists fled from the Spanish army to Antwerp.