Moves to prevent the creation of a so-called "Devonwall" constituency have been defeated in Parliament.
Under the proposed Parliamentary Voting Systems and Constituencies Bill, parts of Devon and Cornwall could end up sharing an MP.
An amendment to the bill which would have protected county borders was lost by 315 votes to 257 on Monday.
Cornwall's six MPs voted in favour of the amendment.
Adam Killeya, mayor of Saltash and member of the Keep Cornwall Whole group, said: "Whilst we are pleased that all six Cornish MPs voted to protect Cornwall's border, we are bitterly disappointed it was not enough.
"We will fight on, and we will keep fighting, to protect Cornwall's distinct history, culture and issues."
Dick Cole, leader of Mebyon Kernow, commented: "We believe the government is wrong to have rushed through this under-scrutinised and self-interested bill, at great cost to communities and parliamentary representation."
Under the new bill, all constituencies would be required to have roughly the same number of voters.
That would mean Cornwall would end up sharing at least one constituency with Devon, opponents claim.
One possible constituency could incorporate two sides of the River Tamar, which bounds parts of Devon and Cornwall.
Campaigners say the border has stood for more than 1,000 years since a treaty between King Athelstan of Wessex and King Hywel of Cornwall.
The Boundary Commission has until 2013 to make its final recommendations on constituency changes.