Los Blancos have lifted the famous trophy three times in a row, and four times in the last five years, but they are now embarking on a new era following the loss of their manager and star player in the summer.
The reigning champions look a little different - weaker, some would say - compared to four months ago when overcoming Liverpool 3-1 in Kiev to add yet another European crown to their growing collection.
Zinedine Zidane stepped aside shortly after that famous night in Ukraine, reportedly because of a row with president Florentino Perez over transfers, and the club's undisputed star performer in Europe, Cristiano Ronaldo, soon followed by joining Juventus in a £100m deal.
No wonder, then, that some bookies have Madrid down as far as fifth favourites to go all the way this time around, behind Manchester City, Barcelona, Paris Saint-Germain and, thanks to the power of Ronaldo, Italian champions Juventus.
The early stages of Julen Lopetegui's tenure have been positive, though, with the sacked Spain boss seeing his side claim 10 points from the first 12 on offer in La Liga. Home wins over Getafe and Leganes, as well as victory away at Girona, have been followed up by a 1-1 draw at Athletic Bilbao at the weekend.
Those dropped points at San Mames, with Isco cancelling out Iker Muniain's earlier opener, allowed Barcelona to move two points clear at the summit, and already it looks as though a third title in 11 seasons may be out of reach if Barca push on.
That is a hugely disappointing domestic record for a side of Madrid's stature, but there can be no complaints about their European exploits in recent years, having reached the semi-finals or better in each of the last eight seasons.
Madrid are not exactly unbeatable, though, as two runners-up finishes in the last two group stages shows, and they have already lost once in Europe this term, going down 4-2 to rivals Atletico Madrid in the UEFA Cup final.
They have won 34 of their last 42 home games in the Champions League, however, losing just two, and are rightly considered the favourites to win this intriguing Group G opener.
Recent form (all competitions): LWWWD
Roma enjoyed one of their finest ever European runs last time out in reaching the semi-finals of the Champions League, overcoming many peoples' favourites in Barcelona in the process before losing to Liverpool in the last four.
The Giallorossi memorably staged a three-goal comeback on home soil after losing 4-1 to Barca in the first leg at Camp Nou, producing one of the standout results in the competition's illustrious history.
It was not to be for Eusebio Di Francesco's men in the end, but they will have another crack at it this season, while also trying to pull off the unthinkable by ending Juve's domestic dominance.
Roma finished third in Serie A last season to reach the Champions League group stages for an 11th time, and a fourth time in five years. Having topped a group containing Atletico Madrid and Chelsea in 2017-18, the Giallorossi will be confident of claiming at top-two finish in Group G this time around.
Falling to defeat at the hands of Madrid will not define Roma's fate. Instead, they have to come out on top in double-headers against CSKA Moscow and Victoria Plzen over the next three months.
The biggest problem for the Italian side has been winning away from home on the continent, having lost all three knockout-round fixtures outside of Roma last season. Despite away defeats to Shakhtar Donetsk and Barca, though, they still made it through to the semis.
Going further back, it is four successive away losses in the Champions League and just three wins in seven in UEFA competitions; their most recent victory away from the Stadio Olimpico coming against Qarabag almost exactly a year ago.
If De Eusebio's charges are to get off to the dream start by claiming a positive result at the Bernabeu, they must put their stuttering Serie A start behind them, with their opening-day win at Torino being followed up by draws to Atalanta and Chievo, on top of a defeat against AC Milan.
Recent form (all competitions): WDLD
Isco and Marco Asensio are competing for a spot on the left of Madrid's all-star attack, which is likely to be spearheaded by Karim Benzema following his bright start to the season - five goals in five games for the Frenchman.
There could be a return for Casemiro in defensive midfield, meanwhile, with Dani Ceballos making way, and Lopetegui also has a decision to make in goal - will it be Keylor Navas or summer signing Thibaut Courtois who gets the nod?
In terms of the visitors, they welcomed Alessandro Florenzi back from injury against Chievo following a few weeks on the sidelines, and the versatile full-back is in line to start at the Bernabeu.
Edin Dzeko will lead the line, 18 months on from netting a hat-trick in Roma's 4-0 success at Villarreal in the Europa League last 32 - the only time his side have avoided defeat in their last five visits to Spain.
De Eusebio has no fresh injury concerns, in fact, so he may well go with the same XI that played out a 2-2 draw with Chievo at the weekend.
Real Madrid possible starting lineup:
Courtois; Marcelo, Ramos, Varane, Carvajal; Modric, Casemiro, Kroos; Asensio, Benzema, Bale
Roma possible starting lineup:
Olsen; Florenzi, Manolas, Juan Jesus, Kolarov; Pellegrini, N'Zonzi, Cristante; Under, Dzeko, El Shaarawy
Head To Head
These two sides have become familiar with one another in the 21st century, as this will be their 11th encounter since their first ever showdown in September 2001.
The first six matches came in the group stage, with Madrid picking up 13 points from a possible 18, but it was Roma who came out on top in the 2007-08 last 16, prevailing 4-2 on aggregate.
More recently, Los Blancos saw off their Italian opponents two years ago en route to lifting the trophy in Milan, winning both legs 2-0 thanks in large to the brilliance of Ronaldo.
We say: Real Madrid 2-0 Roma
Real Madrid can often take time to get going in the Champions League and Roma are not exactly the easiest of opening-game opponents for the reigning champions. The recent UEFA Super Cup loss to Atletico Madrid was just Los Blancos' fourth in 33 European outings, however, with 22 of those ending in victory, and they will be expected to hit the ground running in this mouthwatering fixture.