The centrist ANO (YES) movement led by populist billionaire Andrej Babis, dubbed the ‘Donald Trump of Europe,’ is the front-runner heading into the election.
Polls show he is likely to become the next prime minister despite allegations of fraud linked to EU subsidies.
Mr Babis has been critical of the European Union; he opposes the EU’s quota system on redistributing refugees and setting a date for adopting the euro.
Two days of balloting that started on Friday are being held to fill 200 seats in the Czech Republic’s lower house of Parliament.
Voting will finish on Saturday afternoon and results are expected late in the day.
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Eight parties and groupings are in line to win seats.
The Central European country has enjoyed rapid growth, a balanced budget and the lowest unemployment in the European Union, but voters have grown tired of traditional political players, giving rise to Mr Babis and other protest parties.
As many as nine parties had a chance of winning seats in the 200-member lower house, possibly complicating coalition-building for the victor.
ANO has maintained its rhetoric of opposition to the ruling system despite serving in the outgoing government along with Prime Minister Bohuslav Sobotka’s centre-left Social Democrats and the centrist Christian Democrats.
Mr Babis’ attitude towards Europe raises the prospect he may join Hungary and Poland on a collision course with the bloc.
However, he also praises EU membership and lacks the illiberal ideology seen in right-wing governments in Budapest and Warsaw.
The billionaire has stayed popular despite attacks over conflicts of interest from his food, chemical and agriculture business holdings, which were placed in a trust while in office.
He also faces police charges he illegally received a two million euro EU subsidy when he ran his empire, worth an estimated $4 billion, before entering politics. He has denied wrongdoing.
But ANO has won support from both right and left with pledges to boost investments into shoddy roads, turf out corrupt politicians and reject any EU-wide schemes to resettle migrants from the Middle East and Africa.
He regularly takes swipes at Brussels, which plays well with eurosceptic Czechs and although immigration to the Czech Republic is virtually non-existent, fear of it has played a part in campaigning, with most parties taking a similar tough stance.
The anti-immigrant mood mirrors similar trends in neighbouring countries. Parties opposed to immigration did well in Germany’s election in September and in Austria’s last week.