Band & Brown stalwart Graz Belli, who has been with the agency since 1997, is leaving along with head of commercial brands Mark Lowe at the end of November.
The news follows 12 staff leaving the agency in recent weeks. The 12 departures were a mixture of voluntary and compulsory redundancies in August.
The new agency is scheduled to launch in January.
Details and the name of the new agency have not been revealed, but Belli said: 'I have achieved what I wanted working for someone else, and now it's time for something new.
'The old agency model is dead - it needs some enlightened thinking and that is what we are going to offer.'
Belli insisted the break with Band & Brown was 'really amicable'.
Band & Brown planning director Fiona Longhurst will take up the role of MD once Belli has left. CEO Nick Band explained that the redundancies were due to the COI's comms freeze. 'When the COI went to the wall, we lost about a million pounds worth of fee income. We made some redundancies then,' said Band.
Belli joined the agency as a graduate trainee in 1997 and subsequently worked her way up to the role of MD in 2008.
In a profile interview , Belli said her aim was for PR to lead clients' brand comms ahead of other marketing disciplines. 'PR has always been subordinate, but now it is time for PR to redefine itself,' she said.
The news of Band & Brown's job cuts follows similar agency redundancies at public sector-focused agencies Kindred and The Forster Company, as a result of the COI's comms freeze.
Last week, it was revealed that 24 Kindred staff members have acquired the public sector specialist.
MD Nick Mustoe signed a deal last Wednesday that saw the staff acquire Kindred's trade and assets from former owners Tribal Group. Mustoe made a 'conservative estimate' that Kindred would make £600,000 profit in 2011.