Manchester United face a real test at the London Stadium as they attempt to underline their Premier League title credentials.
The Red Devils finished gameweek four on top of the table and with renewed vigor following Cristiano Ronaldo's return, but a Champions League defeat may have put a dent in their confidence.
West Ham, meanwhile, have lofty aspirations of their own and they look easily capable of achieving them.
When, where and how to watch
When: Sunday, September 19, 2:00PM BST
Where: London Stadium
How to watch: Sky Sports
West Ham vs Man Utd best bets
(All text odds are correct at time of publication and are subject to change)
West Ham will have to make do without star man Michail Antonio after he was sent off in their previous Premier League game against Southampton.
That might see Jarrod Bowen pushed into a more advanced position with recent arrivals Nikola Vlasic and Alex Kral pushing for starts.
Beyond that, though, West Ham have no real selection problems.
Manchester United have a few absentees, with Edinson Cavani, Marcus Rashford, and Alex Telles still out. Scott McTominay also remains a doubt.
However, Fred is back and available, and Anthony Martial could be pushing for a recall.
Aaron Wan-Bissaka was sent off for Man Utd in midweek but he is available as his suspension will only apply to the Champions League.
Man Utd 1-0 West Ham (Premier League - March 14, 2021)
Man Utd got the three points when these two sides last met, but it was a very tightly contested affair.
A young Red Devils side toiled away against a well-drilled West Ham unit who possessed some real punch on the break.
In the end it took a Craig Dawson own-goal shortly after half-time to settle it.
Man Utd 1-0 West Ham AET (FA Cup, February 9, 2021)
It was an even tighter contest when they played each other just a month earlier, but it was again Man Utd who found a way to win.
The sides met in an FA Cup clash and both put out their full-strength teams, and 90 minutes of football couldn't separate them.
Sadly for West Ham, though, substitute Scott McTominay could, with him hitting the winner midway through the first period of extra time.
West Ham 1-3 Man Utd (Premier League, December 5, 2020)
Man Utd's recent hoodoo over former boss David Moyes was again on show in this fixture last season.
It all looked like it was going well for the Hammers when Tomas Soucek handed them a first-half lead.
West Ham vs Man Utd head-to-head (Premier League)
West Ham wins: 7
Man Utd wins: 30
West Ham goals: 45
Man Utd goals: 99
West Ham at it again
There is no question that West Ham had a magnificent season in 2020/21, although success is usually harder to back up in the Premier League than it is to attain.
They have started this season impressively, though, and are yet to lose a match. They also won their Europa League opener in Zagreb in midweek.
That may, though, be a bit of an obstacle for them to overcome in this particular game and beyond.
Last season Moyes was able to prepare his side all week for the Premier League matches, but they're not going to be as prepared with a midweek jaunt to Croatia to fit in too.
However, if they can maintain their energy levels and Moyes can manage the freshness of his more important players, West Ham should be a force to be reckoned with again this season.
Time for Man Utd to deliver
When is it not time for Man Utd to deliver, I suppose? It doesn't matter who they are playing or how much they might be struggling - Man Utd demand success.
That said, there just can't be any excuses anymore for Ole Gunnar Solskjaer. He has been allowed to assemble a squad that should be competing with anyone.
Cristiano Ronaldo is back and spearheading the attack, and Rafael Varane is as good a defender as you'll find anywhere in the world.
Man Utd had a midweek trip to deal with too, of course, but their players are much more experienced in dealing with that and they have had an extra day's rest, so the impact should be far smaller.
West Ham vs Man Utd goalscorer bets
If you are in a really Ronaldo type of mood, you can back him to score a hat-trick at 22/1.
From a West Ham point of view, in Antonio's absence you sense that Jarrod Bowen will carry most of the responsibility to test the Man Utd defence.
He is 9/1 to score the first goal and 4/1 to score anytime.
Set pieces are also likely to play a large part of West Ham's attacking arsenal, and that brings Tomas Soucek into play - particularly at 12/1 to score first and 5/1 anytime.