Liverpool mayor Joe Anderson is lobbying Government to prevent hundreds of millions of pounds of European funding being lost in the next round of ERDF.
The move follows the Government's decision to take £650m of European Union funding which the European Commission had awarded to England for 2014 – 2020 and reallocate it to Scotland, Wales and Northern Ireland.
It includes an estimated £350m which the European Commission had ring-fenced for poorer areas known as transition regions such as Liverpool city region.
Liverpool had expected to receive around £400m from 2014-2020 – but following the Government's amendments there are fears this could be slashed by up to a half.
Mayor of Liverpool and chairman of Liverpool City Region Cabinet, Cllr Joe Anderson, said: "European funding has been critical to the successful regeneration of the city region over the last couple of decades.
"Everywhere you look, from the Arena & Convention Centre to the School of Tropical Medicine, John Lennon Airport to the Cruise Liner Terminal, there are physical reminders of the difference that funding from the European Union has made.
"It has created helped create thousands of jobs and boosted the economy to the tune of many tens of millions of pounds.
"Our big fear is that we could lose a massive chunk of the share of funding we expected to receive as the extra money allocated for Scotland, Wales and Northern Ireland will come specifically from cash allocated for more deprived areas including ours.
"In effect this means that we will lose out while wealthier and more prosperous areas of England, many of which have never previously received EU funds, will gain at the expense of poorer areas.
"I outlined my concerns to European Commissioners during a visit to Brussels earlier this year, and we are now taking our case to the UK Government."
From 2007-2013 Liverpool City Region received around £460m from the European Social Fund and European Regional Development Fund.
Representatives from Liverpool City Region will join representatives from Sheffield City Region in meeting business minister Michael Fallon on Monday to argue that a safety net should be applied to the funding allocations to limit the reduction.