London Irish's unbroken 20-year membership of the English rugby elite will effectively end if they are beaten by Harlequins on Sunday.
Should Quins triumph, then only the unlikely event of Bedford winning this season's Greene King IPA Championship would keep Irish afloat.
Bedford's fellow Championship title hopefuls Bristol, Yorkshire Carnegie and Doncaster have all met minimum standards criteria to play in the Aviva Premiership next season.
The trio, plus Bedford, will be involved in opening Championship play-offs this weekend, but Bedford did not apply to have their ground audited and would not be promoted if they win the Championship, offering Irish a lifeline, although Bristol are red-hot title favourites.
Irish, European Cup semi-finalists eight years ago, have been ever-present in the Premiership since its launch in 1997, having returned to English rugby's old top-flight first division a year earlier.
But they go into a Madejski Stadium clash against Quins seven points adrift of 11th-placed Newcastle with just two games left. The Falcons visit league leaders Saracens on Sunday.
"We have enjoyed a longer preparation for Sunday's game, and that has allowed us to welcome a couple of injured players back into the match-day squad," Irish head coach Tom Coventry said.
"The players know the importance of the contest and have worked hard in training. It was a tight match at the Twickenham Stoop a few weeks ago, and I envisage Sunday's game being similar."
Newcastle will head to Allianz Park, facing a Saracens side without the likes of Owen Farrell, Alex Goode, George Kruis and Billy Vunipola as rugby director Mark McCall makes several changes following last weekend's European Champions Cup semi-final win against Wasps.
A Newcastle victory would condemn Irish to finishing bottom, whatever the Exiles achieve against Quins, and Falcons' front-row coach Micky Ward said: "We are not mathematically safe, but we are in a far better position than London Irish and a far better position than we were a couple of weeks ago.
"We are nearly over the line, and it is down to us now. It is in our own hands. We can decide it this weekend by taking points at Saracens and putting it beyond all doubt.
"Technically, we need to stick to our systems, and we have got to go down there with a mindset and an intensity to really just fly into them.
"We can have the best attacking shape in the world, but if we can't win the ball at the set-piece and breakdown, it is a waste of time. We need to be physically and mentally on it, and basically just smash into them at every opportunity."
Also on Sunday, play-off qualifiers Exeter and Wasps meet again just three weeks after a pulsating Champions Cup quarter-final encounter that Wasps won 25-24, with this weekend's victors putting themselves in pole position for a home Premiership tie next month.
Exeter head coach Rob Baxter said: "You can see from our results this season, plus the consistency we have shown, it has driven us into the top four with two games remaining, which is pretty good going.
"That said, we should want more. Once you tick off top six, then top four, you should want more, and I am not afraid to say we want a home semi-final and we want to win the Premiership. Why not?
"Right now, we are two games away from being Premiership champions regardless of what happens over these next two weeks (against Wasps and Harlequins). Therefore, let's start talking and feeling like we can challenge ourselves and put pressure on ourselves to now deliver."
Leicester will complete the play-off picture alongside Saracens, Wasps and Exeter if they see off Welford Road visitors Worcester on Saturday, while Northampton need victory over Bath at Franklin's Gardens to stay on course for a top-six finish and automatic Champions Cup qualification next season.