Two much-loved music venues in Manchester and two in Hull have been shut down, after four months of enforced closure.
The operator of Manchester's Deaf Institute and Gorilla said it would not be able to reopen those venues.
And the companies behind the Welly and the Polar Bear in Hull have gone into administration.
The announcements came as the Southbank Centre in London said up to 400 roles have been put at risk of redundancy.
The live entertainment industry is feeling the effects of being closed to the public since coronavirus restrictions were imposed in mid-March.
The Deaf Institute and Gorilla have been popular with fans and artists over the past decade. The Deaf Institute has hosted the likes of Florence & the Machine, Haim and Tame Impala, while Gorilla has witnessed shows by Blossoms, Foals and Sam Fender.
"This difficult decision has been made against the backdrop of Covid 19 and the enforced closure of all of our sites and with continued restrictions upon opening of live music venues," said Roy Ellis, chief executive of venue operator Mission Mars.
"We appreciate that these music destinations are well loved and have provided an early stage for many acts in the North West and are therefore well known in the world of music."
They encouraged any "industry and music entrepreneurs who might be interested in this as an opportunity" to get in touch.
Sacha Lord, night time economy adviser for Greater Manchester, said he "fully" expected Deaf Institute and Gorilla to reopen "in time".
He said he and Greater Manchester mayor Andy Burnham would "do everything we can to find new operators", adding: "We need grass roots venues across the whole of our City Region."
In Hull, The Welly has played host to the likes of U2, Pulp and The Housemartins over its long history.
The Welly and the Polar Bear were closed after two companies under the VMS Live umbrella were placed into administration.
Responding to the news, The Music Venues Trust said: "We have been warning for months that the situation faced by grassroots music venues was unsustainable and would result in the closure of spaces people love and artists need unless there was concerted, strategic action.
"That action now needs to be accelerated to prevent hundreds of other venues from being lost right across the country."
Meanwhile, a spokesperson for The Southbank Centre told The Guardian that two-thirds of its staff could be made redundant
A statement said: "It is with great sadness that the Southbank Centre announced that up to 400 roles have been put at risk of redundancy as part of a comprehensive management action plan designed to stem the financial losses being incurred as a result of Covid-19, and to help safeguard the future of the UK's largest arts centre."
And a major drive-in tour featuring the hit musical Six and acts like Kaiser Chiefs, Dizzee Rascal and The Streets has been cancelled due to uncertainties over local lockdowns.