The Greek outfit recorded a 2-0 aggregate win over Neftchi Baku in the last round of the competition, while Ludogorets have beaten Shakhtyor Soligorsk and Mura to advance to this stage.
Olympiacos secured their second successive league title last season, finishing with 90 points from 36 matches, which saw them qualify for the second qualifying round of the Champions League.
The Red-Whites recorded back-to-back 1-0 wins over Neftchi Baku in the second qualifying round, and the new Greek league season does not start until August 20, meaning that they can fully focus on this competition.
Pedro Martins's side have plenty of history in the Champions League, most recently competing in the group stage of last season's competition against Porto, Manchester City and Marseille.
Olympiacos actually reached the last-16 stage of last season's Europa League, losing to Arsenal over two legs, and they will fancy their chances of securing top-level European football for the 2021-22 campaign.
The Greek giants, as mentioned, will not start their league campaign until later this month, meaning that they only played two competitive matches in July, which could help or hinder them as the race to make the group stages of the Champions League reaches its climax.
Ludogorets, meanwhile, started this season's Champions League in the first qualifying round, where they beat Shakhtyor 1-0 home and away to advance to the next stage of the competition.
The Bulgarian outfit were held to a goalless draw by Mura in the first leg of their second qualifying round contest, but a 3-1 victory in the reverse fixture allowed them to set up the clash with Olympiacos.
The Eagles competed in the group stage of last season's Europa League but struggled to make an impression, losing all six of their Group J fixtures against Tottenham Hotspur, LASK and Royal Antwerp.
Ludogorets did compete in the group stage of the 2016-17 Champions League, though, and actually finished third in Group A, which included both Paris Saint-Germain and Arsenal, before losing to Copenhagen in the last-32 stage of the Europa League, having dropped into that competition.
The visitors are two games into their domestic season and have picked up maximum points to top the division, with Valdas Dambrauskas's side recording a 3-0 win over CSKA 1948 Sofia on Saturday.
Olympiacos have no injury or suspension concerns leading into Tuesday's contest, and it would not be a surprise to see Martins select the same XI that took to the field for the second leg against Neftchi Baku.
As for Ludogorets, there are likely to be a number of summer arrivals in the starting XI, with Kiril Despodov, Olivier Verdon, Igor Plastun and Bernard Tekpetey all set to feature from the first whistle.
Elvis Manu came off the bench to find the back of the net in his side's last European match but is expected to be among the substitutes once again, with Dambrauskas unlikely to spring any surprises.
Olympiacos possible starting lineup:
Tzkolakis; Lala, Semedo, Markovic, Ba, Cisse; Valbuena, Sourlis, Malong, Masouras; Koka
Ludogorets Razgrad possible starting lineup:
Kahlina; Ikoko, Plastun, Verdon, Nedyalkov; Cauly, Goncalves, Santana; Despodov, Sotiriou, Tekpetey
We say: Olympiacos 2-1 Ludogorets Razgrad
Ludogorets are now on a run of three straight wins in all competitions, while they have been victorious in six of their seven competitive matches this season. Olympiacos were hardly convincing in the second qualifying round, but we are still expecting the Greek outfit to secure a first-leg advantage.
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