A “no deal” Brexit will cost Tayside and Fife billions of pounds in lost economic growth, according to a London School of Economics study.
The analysis found the area will be £3.7bn worse off over five years than if Britain remained in the EU.
The Liberal Democrats said the figures are a stark warning of the serious damage Scotland faces from crashing out of the EU.
A departure from the bloc in which the UK stays in the single market and customs union – known as a soft Brexit – would see Courier Country lose £2.2bn in economic output over that period.
Vince Cable, the Liberal Democrats leader, said the figures show the UK Government must commit to the staying in the European single market, as well as the tariff-free trading union.
“This work by the LSE brings out the extent to which Scotland would be seriously damaged economically by a no-deal Brexit,” he said.
“These economic modelling exercises are necessarily approximate, but if anything they understate the damage once we take into account the knock-on effects.
He added: “The UK Government must guarantee our membership of the single market and customs union.
“This is precisely why the Liberal Democrats, alone among political parties, are campaigning for an exit from Brexit by offering the people a vote on the final deal.”
Across Scotland, the cost failing to secure an agreement with Brussels is estimated at £30bn over five years, compared with £17bn for a soft Brexit.
The price of a no deal is £2bn in Tayside and £1.7bn in Fife, according to the LSE’s Centre for Economic Performance. Together that represents 5% of the local economy.
A spokesman for the UK Government said: “We are committed to securing a good deal with the EU that works for the whole of the UK, through a bold and ambitious Free Trade Agreement.
“We are engaging extensively with businesses and organisations across the country, and will continue this work throughout the exit process.
“Through the UK Government’s modern Industrial Strategy we will look to build on the diverse strengths of all of the UK’s cities and regions.”
Meanwhile in the Commons, the SNP Westminster group leader Ian Blackford urged Mrs May to take the “no deal” Brexit option off the table, adding membership of the single market and customs union were “absolutely critical”.
Mrs May said that full membership of the single market and customs union “go with the jurisdiction of the European Court of Justice and freedom of movement”.
She added: “These are issues which were voted against when people voted to leave the European Union – they would effectively mean that we would remain in the European Union and we are going to leave in March 2019.”