The two sides played out a 1-1 draw in Russia in their first group-stage meeting back in September, with Philippe Coutinho scoring a first-half equaliser to cancel out Fernando's opener.
Victory at home for leaders Liverpool would ensure Jürgen Klopp's side go through to the next round as Group E winners, while a draw would still be enough to progress.
We've picked out three key battles that could help decide tonight's match at Anfield...
Sadio Mane vs Andrey Yeshchenko
A title winner in both Russia and Ukraine, veteran right-back Yeshchenko said the game against Liverpool in Moscow was the best of his career.
The 33-year-old will be determined to match his performance from the first clash, in which he also registered one of Spartak's two shots on target, but the Reds have scored three goals or more in seven of their last eight games and he can expect to be busy.
The No.38's battle with Mane could be pivotal. The Reds forward played a slick one-two to set up Coutinho for Liverpool's equaliser in Moscow and also laid on great chances for Roberto Firmino and Mohamed Salah.
In the opposite full-back slot, Dmitri Kombarov will not be available after suffering a broken rib and so Giorgi Jikia should slot in at left-back following his return from suspension.
Jordan Henderson vs Denis Glushakov
Glushakov is Spartak's leader and club captain. He has become pivotal for club and country in recent years and is capable of scoring goals with dangerous late runs into the penalty area.
The box-to-box midfielder's strikes tend to be crucial ones too. His cool finish in injury-time during the weekend's 1-0 win at Arsenal Tula added a seventh victory to Spartak's 12-match unbeaten run in the Russian Premier Liga.
He scored eight goals in 24 starts last season and was one of the key figures in Spartak winning their first title in 16 years.
The 30-year-old will likely be battling against fellow skipper Henderson in the centre of the park as he attempts to stop the Reds' supply line. Henderson leads the Liverpool midfield with 238 completed passes in the Champions League this term.
Joe Gomez vs Quincy Promes
Spartak's Dutch forward Promes is a close friend of Liverpool's Gini Wijnaldum, who picked out his Netherlands team-mate as a key threat at Anfield.
"He is a player that needs a lot of thought," Wijnaldum told uefa.com. "I think he has already showed that in their league games when he has scored and played. He has scored a lot of goals and given a lot of assists.
"Spartak had a few players missing the last time we played, including Promes, but now they are stronger."
The 25-year-old has consistently been the best player in Russia and is Spartak's top scorer for the last three seasons. Playing predominantly on the left flank this term, he has 13 goals and eight assists in 23 games.
Liverpool defender Gomez, who missed Saturday's 5-1 win at Brighton and Hove Albion due to illness, will be tasked with halting Spartak's main attacking threat if he is fit to return and selected.