On the field, Barca should have little problem sweeping aside an Olympiakos side without a point in the Champions League so far this season to consolidate their position atop Group D.
However, how Barca's fans will react to a tumultuous few weeks of political tension in Catalonia is less predictable with the support split like the rest of society on wealthy northeastern region of Spain.
Chants in favour of independence are common at the Camp Nou from a section of the Barca fanbase, most notably in the 17th minute to mark the fall of Catalonia in the Spanish War of Succession in 1714.
Leading Barca players such as Gerard Pique and Andres Iniesta called for politicians on both sides of the independence debate to negotiate in the wake of the October 1 referendum.
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As Spanish riot police fired rubber bullets and seized ballot papers leaving 92 injured, among nearly 900 who sought medical attention that day, Barca beat Las Palmas 3-0 behind closed doors.
Club president Josep Maria Bartomeu insisted he tried to have the match abandoned, but instead settled for showing their opposition by playing the match in an empty 99,000 capacity Camp Nou.
A standoff has ensued with Spanish Prime Minister Mariano Rajoy calling on Catalan leader Carles Puigdemont to clarify if he has declared independence for Catalonia on the basis of the referendum, deemed illegal by the Spanish government.
"What we like is playing and enjoying ourselves in a spectacular atmosphere like today," said Iniesta after Barca's 1-1 draw at Atletico Madrid on Saturday.
Barca's first visit to the capital since the escalation of the political divide was expected to provoke a hostile welcome for the visitors.
"It was a great game, in a great atmosphere, in a great stadium," said Barca boss Ernesto Valverde.
Despite a series of distractions on and off the field, including the loss of Neymar to Paris Saint-Germain and calls for Bartomeu to resign on top of the Catalonia crisis, Barca have started impressively under Valverde.
A run of nine straight wins in La Liga and Champions League was ended on Saturday, but Barca are heavy favourites to get back to winning ways against one of Valverde's former clubs.