They will meet tomorrow at Deepdale for the 40th time since the 1999/2000 season.
There have been only three seasons in that period when they have not played.
The first of those was when United made it to the Premier League in 2006/07 .
Then PNE had a two-year head start over the Blades in getting promoted back to the Championship – they had been relegated together in May 2011.
Chris Wilder brings his side to Lancashire in third place and firmly in the hunt for automatic promotion.
They had a setback last week when beaten 3-2 at home by Bristol City.
If they felt low after that, it could be balanced somewhat by the high of winning 1-0 at Leeds in their previous game.
The Blades are two points behind second-placed Leeds who come to Deepdale next Tuesday night.
In Preston boss Alex Neil, they have an admirer of their system – ‘unique’ is the word Neil uses to describe the use of overlapping centre-backs.
“Sheffield United have played a certain style since Chris has been there,” said Neil.
“It is different to anyone else in our division and in all four leagues I would think.
“They have got an unique way of playing which they have done very well to cultivate on the stage where it’s at.
“That is why they’ve had such a good season.
“It’s going to be a tough test for us but our record against Sheffield United is relatively good.
“I know we lost earlier this season at their place when we got back to 2-2 and they then made it 3-2.
“We managed to beat them twice last year and they’ve all been really tight games. I don’t expect this game to be any different.
“What makes them unique is that their centre-backs go and overlap.
“Very few centre-backs are comfortable doing that but they have got Martin Cranie, Jack O’Connell, Chris Basham and Enda Stevens who can do that job.”
At the other end of the pitch, Wilder’s men can boast the Championship’s second highest scorer in Billy Sharp.
The striker has scored 23 goals in the league and one in the League Cup.
At 33, the Blades skipper shows little sign of slowing down.
Like PNE were, United were on a strong run of form before losing to Bristol City last week.
It was a game they led 1-0 and 2-1 in, before the visitors turned things on their head with two late goals.
Wilder’s outfit had been unbeaten in 10 games, a run which included seven wins.
Looking at the bigger picture, Wilder said: “We shouldn’t allow a bad day at the office to wreck what we’ve done.
“There’s still an awful lot of football to be played yet.”