Prime Minister Anthony Albanese says anything less than a "massive majority" in the Aston by-election would be a blow to the Liberals.
Melbourne barrister and councillor Roshena Campbell is widely expected to win Saturday's by-election, retaining the seat vacated by former minister Alan Tudge for the Liberals.
Mr Albanese said history showed by-elections swung against sitting federal Labor governments by five to six per cent, and no government had won a by-election off an opposition in more than 100 years.
"The Liberals should retain Aston with a massive majority," he told reporters in Brisbane on Friday.
"The fact that the Liberal Party are having to spend so much money, and they have massively out-spent Labor in this by-election, in order to hang on to one of their heartland seats says everything about the state of the Liberal Party brand."
Federal leader Peter Dutton was a key factor in the erosion of the Liberal branch, Mr Albanese said, comparing him to a Winnie-the-Pooh character.
"Federally, they just sit there and vote no to everything," he said, noting a number of government wins on legislation during the parliamentary sitting fortnight.
"They are the Eeyores of Australian politics and Peter Dutton is the angry Eeyore - he just sits there 'woe is me, the sky is falling in', every time an initiative is put forward."
Labor candidate Mary Doyle is a former union organiser and cancer survivor who contested last year's federal election.
Mr Dutton, who campaigned in the seat in Melbourne's east with Ms Campbell on Friday, said he expected his party to retain the seat in a tight result.
The Liberals hold the seat on a 2.8 per cent margin after a massive swing against the party at last year's election.
"Every decision Labor has taken economically over the course of the last 10 months has driven up the cost of living pressures on families and on small businesses," Mr Dutton said.
"There's an opportunity here to send a message to Labor, that it's just not good enough because living pressures continue to go up."
Ms Campbell hopes her experience as a barrister and Melbourne City councillor will position her to win the seat.
"They (Labor) have shown they are happy to take the outer east for granted," she said.
Mr Albanese said Ms Doyle would be a strong voice in government if elected.
Monash University's Dr Zareh Ghazarian said the contest would have huge implications for national politics.
"It will be a test of whether the Liberal Party can reconnect with voters who abandoned it at the last federal election," he said.
"It will also be a test of whether Labor is still carrying the political momentum that saw it win the Victorian and NSW state elections in recent months."
The Australian Electoral Commission is concerned about a possible low voter turnout, given the lower than expected interest in early voting.
Other candidates for the seat are project manager Angelica Di Camillo (Greens), software engineer Owen Miller (Fusion) and libertarian advocate Maya Tesa (independent).
