Having held their own in the group stage last autumn, Sheriff trail 2-1 from the first leg in Transnistria, and need a positive result to progress past a home side still unbeaten this term.
Match preview
A proud 16-match undefeated run ended for Sheriff last week, as the perennial Moldovan champions lost out to their rivals for a place in the playoff round of Champions League qualifying - the final step of the journey back to the group stage.
Head coach Stjepan Tomas took the reins earlier this summer, and was immediately under pressure to replicate the run enjoyed by Yuriy Vernydub's side last year, when they gatecrashed the group stage and beat both Shakhtar Donetsk and Real Madrid.
Starting qualification in the first round, at the start of July, Sheriff needed only one goal to get the job done against Zrinjski over two legs, and they then repeated the trick against Maribor in the second round.
However, after four clean sheets, Tomas saw his team capitulate in the second half last Tuesday, as they let a one-goal advantage slip at Zimbru Stadium, where they host their European home games - nearly 50 miles away from Tiraspol, in Chisinau.
In fact, that was where Sheriff started the defence of their domestic crown last week, as they drew 1-1 at Zimbru. Following up with a 3-1 win at Sfintul Gheorghe, they already sit top of the Moldovan National Division, but now return their thoughts to continental matters.
Viktoria Plzen, meanwhile, have mirrored their opponents' league results so far, and after also opening their campaign with a draw - 2-2 away to Teplice - they won 2-1 at home against FK Pardubice on Saturday.
As Czech champions for the first time in four years, and the sixth time in all, Viktoria started their qualification journey in the second round, with a thumping 7-1 aggregate victory over Finland's HJK.
On that occasion, Michal Bilek's men also won the first leg away from home 2-1 - as they did against Sheriff last week, with second-half strikes from Tomas Chory and Pavel Bucha - before wrapping things up back in Plzen.
The club's most recent appearance in the Champions League group stage appearance came in the 2018-19 season, when they lost four of their six matches in a group featuring Real Madrid, Roma and CSKA Moscow.
This time last year, Viktoria were eliminated at the playoff round of the inaugural Europa Conference League, but they are now well-placed to take a step closer to the promised land this week, with a place among Europe's elite coming ever closer.
Viktoria Plzen Champions League form:
Viktoria Plzen form (all competitions):
Sheriff Tiraspol Champions League form:
Sheriff Tiraspol form (all competitions):
Team News
With Tuesday's second leg in mind, Michal Bilek opted to make sweeping changes against Pardubice at the weekend, and five changes to the lineup perhaps understandably produced an unconvincing display.
Among those missing was captain Lukas Hejda, due to suspension, but the centre-back will return to the XI in Europe, as Filip Kasa makes way.
Albanian midfielder Kristi Qose and Brazilian winger Cadu should also drop out, with the experienced trio of Vaclav Pilar, Jan Sykora and Pavel Bucha coming in. After scoring again on Saturday, Jan Kliment will lead the line in attack.
Meanwhile, Sheriff may contemplate changes to the team which lost last week on home soil, and Burkinabe wide man Abou Ouattara is among several players pushing for promotion from the bench.
Former Dinamo Zagreb striker Iyayi Atiemwen, recently ruled out by injury, could make his Champions League debut for the visitors, but his fellow Nigerian Rasheed Akanbi and Dutch forward Kay Tejan are the current incumbents up front.
Viktoria Plzen possible starting lineup:
Stanek; Pernica, Hejda, Havel; Sykora, Bucha, Kalvach, Pilar; Kopic, Kliment, Chory
Sheriff Tiraspol possible starting lineup:
Abalora; Guedes, Kiki, Radeljic, Kpozo; Badolo, Kyabou, Lushkja; Ouattara, Tejan, Akanbi
We say: Viktoria Plzen 2-1 Sheriff Tiraspol (Viktoria Plzen win 4-2 on aggregate)
Given their apparent ability to score goals at will this season - they have found the net at least in all five of their competitive games so far - the hosts are unlikely to be perturbed if Sheriff pull level on aggregate at some stage.