The Nieuw-Vlaamse Alliantie (New Flemish Alliance or N-VA) won the most votes in a vast swathe of districts in the Dutch-speaking region of Flanders, including the port city of Antwerp.
The party's leader Bart De Wever was on course to become the city's mayor after the N-VA were on 36% of the vote with most of the votes counted.
"We are the new people's party of Flanders," De Wever told cheering supporters.
Incumbent Patrick Janssens conceded defeat, saying the initiative was now with De Wever to form a coalition. Janssens' alliance of Flemish Socialists and Christian Democrats, both part of the federal government, stood just under 30%.
Antwerp's mayor has been a Socialist, excluding a six-week gap in 1976, since the end of the Second World War.
De Wever's victory will not lead to the break-up of Belgium, but it is likely to have an impact on a national level.
De Wever says he sees Belgium disintegrating gradually.
The three Flemish parties in Prime Minister Elio Di Rupo's six-party coalition suffered losses and their efforts to win back voters wanting more powers for Flanders could undermine their cooperation with French-speaking coalition partners.
The federal government is about to begin difficult discussions to settle the budget for 2013.
Di Rupo's coalition is on course to pull the public sector deficit down to 2.8% of gross domestic product this year, from 3.7% in 2011, due to some €13 billion of savings and tax hikes.
It is estimated it will need to find a further €4-5 billion to achieve a deficit of 2.15% in 2013, a target made more difficult with economic stagnation or contraction expected this year and very limited growth next.
Belgium's division is as much economic as linguistic. In French-speaking Wallonia the unemployment rate is about twice the level of northern Flanders, where many voters feel they are subsidising left-wing policies of Belgium's south.
A recent study of the VIVES institute of the University of Leuven calculated that including interest the annual transfers between Flanders and Wallonia are about €16 billion.