Northampton boss Chris Boyd has described the cancellation of Saints' Gallagher Premiership clash against Leicester on Saturday as "a bitter pill to swallow".
The east midlands derby at Franklin's Gardens is off after Northampton returned positives in the latest round of coronavirus testing.
The club's training ground has also been closed, Premiership Rugby said in a statement.
It is the fifth Premiership match to be cancelled in just over a fortnight because of Covid-19.
"The health and safety of players, management, staff and match officials is our priority," a Premiership Rugby spokesperson said.
"We wish those who have tested positive at Saints a speedy and safe recovery."
Saints said that the club had returned a number of positive tests and had further players unavailable because of the contact tracing process.
"In close consultation with Public Health England, the match has subsequently been called off and Saints' training also cancelled until the next round of testing – scheduled for Monday, January 11," Northampton said.
"The players involved have already begun a 10-day isolation period in accordance with the guidelines set out by Public Health England."
Northampton's away match against London Irish last weekend was scrapped because of positive tests in the Irish camp.
Saints rugby director Boyd said: "We are incredibly disappointed and frustrated that we are unable to proceed with such an important fixture for the club.
"It is a big blow to have back-to-back matches cancelled, as we had hoped to pick up some momentum again following an important win on Boxing Day.
While this is a bitter pill to swallow, the health and safety of the players, staff and families of everyone at both Saints and Tigers is of course paramount."
"The club has been absolutely rigorous in how we have followed the protocols laid out for us and, despite returning a number of positive tests this week, we were confident that we have more than enough of our squad still healthy and available to play the game if required.
"However, we are following the advice we have been given, which was not to play the game and to close our training facility until next week.
"While this is a bitter pill to swallow, the health and safety of the players, staff and families of everyone at both Saints and Tigers is of course paramount."
Under Premiership Rugby regulations, a panel will now be convened to determine the allocation of points, but the Tigers can realistically expect to be awarded four points and Saints two, with a 0-0 scoreline declared.
It remains to be seen whether any of the remaining five Premiership fixtures this week will be affected.
Premiership champions Exeter also revealed "some" positive Covid-19 tests in camp, but their weekend clash with Bristol at Sandy Park is still scheduled to go ahead.
Chiefs director of rugby Rob Baxter said there had been "a slight impact on the availability of players but not huge".
Asked on Wednesday if he was confident the game will go ahead, Baxter said: "At this stage I'm very confident.
"But experience has told me that every time I've said I am confident about where the Covid scenario is within club rugby, something comes around and the opposite happens."
He added: "When we have anything in the camp Covid-wise, we always try to organise a second round of testing, so we will do that either (on Thursday) or Friday."