Both clubs find themselves in and around the top 24, with the Ukrainian visitors looking to break into the qualifying positions following a first win last time out.
Match preview
Peter Bosz's PSV side continue to set remarkable goalscoring heights, beating Groningen 5-0 at the weekend on their return to action after the international break.
That saw them remain five points clear of Utrecht at the top of the league, with four wins in five, scoring 20 goals in that time, and it is Utrecht who are up next for PSV following this European encounter.
All eyes and focus will be on the Champions League for now though, with PSV sitting in 24th - the final knockout stage spot.
It has been a respectable start in trying circumstances for the Dutch side, because their opening day defeat to Juventus was followed up by further difficult matches with Sporting Lisbon and Paris Saint-Germain, but they were able to hold both to draws.
In their first game as outright favourites in the Champions League this season, Bosz's men thrashed Girona 4-0 last time out, and now have the opportunity to win back-to-back UCL games for just the second time in seven seasons.
That win over the competition debutants moved them up onto five points at the halfway stage, and another five points in their final four games should be enough to sneak them through.
Three points are expected here given that PSV are unbeaten in 12 matches at home - their best run in over 12 years.
The hosts will need to improve on their recent record with Ukrainian clubs if that is to continue though, in what will be a first meeting against Shakhtar, as PSV have lost three of their last four matches against clubs from the country.
Against similar-level sides though, PSV often do perform, because they are unbeaten in their last 10 matches in this competition against clubs who have never featured in a final.
Shakhtar manager Marino Pusic will look to end that streak when he returns to his adopted homeland here, fresh off the back of a 2-1 win over Young Boys on matchday four which has got their campaign up and running finally.
After recording just two shots on target in their first three UCL games of the season, unsurprisingly failing to score, Shakhtar had six against Young Boys on their way to a deserved win, bringing them back into contention to advance.
In all competitions, that result has contributed to a run of five straight wins, which was continued courtesy of a 6-0 demotion of Inhulets at the weekend.
All of those five matches were at home though, and Pusic's side are winless in their previous two as the designated away team, losing at Arsenal and drawing with Dynamo Kyiv, who remain six points ahead of them domestically.
With Bayern Munich, Brest and Borussia Dortmund to come in their final three, Shakhtar will have to spring a surprise somewhere if they are to compete for the top 24, and a win here may be necessary.
That appears difficult when it is taken into consideration that Shakhtar have won just two of their last 14 away games in Europe, and have lost on three of their last four trips to the Netherlands.
PSV Eindhoven Champions League form:
L
D
D
W
PSV Eindhoven form (all competitions):
D
W
L
W
W
W
Shakhtar Donetsk Champions League form:
D
L
L
W
Shakhtar Donetsk form (all competitions):
Team News
PSV are set to be without Luuk de Jong once again here with a minor muscle injury, but that should be no problem if Ricardo Pepi can continue his incredible form.
A hat trick in the win over Groningen at the weekend means that Pepi has now scored 10 goals in his last six starts for club and country, and is set to lead the line again.
Armando Obispo and Hirving Lozano both returned from injury at the weekend to take a place on the bench, but Jerdy Schouten and Joey Veerman remain out, while Sergino Dest is a major doubt.
There are no first-team injuries for Shakhtar at present, with Pedrinho's absence from the squad at the weekend believed to be precautionary.
The Shakhtar defence could look very different to the one that faced Inhulets on Sunday if Pedrinho does return, because Mykola Matviienko and Yukhym Konoplya were also kept in reserve ahead of this one, and should start.
Eguinaldo started in the win over Young Boys on matchday four, and looks set to return to the XI here after netting twice off the bench in the win over Inhulets.
PSV Eindhoven possible starting lineup:
Benitez; Karsdorp, Flamingo, Boscagli, Dams; Til, Mauro Jr, Tillman; Bakayoko, Pepi, Lang
Shakhtar Donetsk possible starting lineup:
Riznyk; Konoplya, Bondar, Matviienko, Pedrinho; Bondarenko, Kryskiv, Sudakov; Zubkov, Eguinaldo, Kevin
We say: PSV Eindhoven 3-0 Shakhtar Donetsk
An impressive win over Girona last time out in this competition shows that PSV have the firepower in attack to progress to the knockouts, and they should fancy themselves to put on a similar show here.