Madrid have had their problems this season, but Santiago Solari's side will enter this week's match off the back of a fine run of form and will be confident of taking an advantage into the second leg at the Bernabeu.
Ajax are present in the round of 16 for the first time since the 2005-06 campaign, but have never won at this stage of the Champions League. Meanwhile, the Dutch giants have lost their last six games against Madrid, conceding 20 times and scoring just twice, which is an indication of their task over the two legs.
It will be the first meeting between the two teams since the group stage of the 2012-13 season. Madrid won 4-1 home and away during that particular campaign, while Ajax have not beaten Los Blancos in a home European match since 1995, when a certain Marc Overmars scored the only goal of the match in Amsterdam.
Not since the 2002-03 campaign have Ajax reached the quarter-finals of the Champions League, while the Dutch outfit have only been victorious in two of their last 14 European matches against Spanish opposition.
That said, Ajax are impressively unbeaten in Europe this season. Indeed, they have won seven of their 12 matches and only finished two points behind Bayern Munich in Group E. The Dutch outfit drew home and away against Bayern, demonstrating that this team is certainly capable of causing Madrid problems.
Erik ten Hag's side will enter this match off the back of a 1-0 defeat at Heracles in the league on February 9. A total of 50 points has left them in second position in the Eredivisie, but they have lost two of their last three league fixtures and are six points off division leaders PSV Eindhoven.
Ajax have incredibly scored 72 times in 21 league matches this season, while they netted 11 times in the group stage of the Champions League. Ten Hag can call upon a number of excellent attacking players and it should be a fascinating battle in Amsterdam on Wednesday night.
Recent form: WDWDWD
Recent form (all competitions): WDWLWL
Madrid have won the last three editions of the Champions League and have been victorious in their last nine two-legged knockout ties in the competition, which is a quite staggering record.
This is Madrid's 23rd Champions League campaign and indeed the 23rd time that they have reached the knockout stage. The 13-time champions have been semi-finalists or better in each of the last eight seasons and are rightly the favourites to progress past Ajax to make the final eight once again.
Madrid lost home and away to CSKA Moscow in the group stages, but still managed to top the section with 12 points. It would be fair to say that Los Blancos have had their problems this season, but it does appear that a corner has been turned in recent weeks.
Solari's team are unbeaten in their last seven matches in all competitions, which has seen them move to within six points of La Liga leaders Barcelona, in addition to make the semi-finals of the Copa del Rey. The capital giants are the favourites to reach the final of the cup, meanwhile, having picked up a 1-1 draw against Barcelona in the first leg of their last-four clash at Camp Nou.
Madrid's 3-1 victory over Atletico Madrid on Saturday was particularly impressive and quite probably the result, along with the draw at Barcelona, that showed that they mean business at this stage of the season.
Los Blancos are not seen as the favourites to win the Champions League this season, but they have only lost six of their last 39 European matches, while they simply cannot be written off due to their incredible success in the competition.
At this stage of last season, Madrid overcame Paris Saint-Germain. The Spanish outfit have won on five of their last six visits to the Netherlands and in their current form, will be extremely confident of picking up an advantage ahead of the second leg at the Bernabeu on March 5.
Recent form: WLWWWL
Recent form (all competitions): WWWWDW
Tadic, who arrived at Ajax from Southampton last summer, has scored 22 times in all competitions for his Dutch club this season and could lead the line on Wednesday night.
Tadic's role in the middle could well see both Huntelaar and Dolberg left on the bench, with Ziyech and David Neres providing the support in the wide positions.
Matthijs de Ligt - believed to be a target for a host of the world's biggest clubs - will start in central defence, while there will also be a spot for Frenkie de Jong, who is heading for Barcelona this summer.
Former Manchester United player Daley Blind is also expected to make the Ajax XI this week.
Isco has also been ruled out with a back and neck injury, but Solari has no fresh injury concerns from the team that overcame Atletico at the weekend.
Ajax possible starting lineup:
Onana; Mazraoui, Blind, De Ligt, Tagliafico; Schone, De Jong, Van de Beek; Neres, Tadic, Ziyech
Real Madrid possible starting lineup:
Courtois; Carvajal, Varane, Ramos, Reguilon; Casemiro, Modric, Kroos; Lucas, Benzema, Vinicius
Head To Head
The two teams have met on 12 occasions in the European Cup. Madrid lead the head-to-head seven wins to four, with only one draw taking place.
Madrid have won each of the last six meetings between the two teams, but Ajax won four straight matches against the Spanish giants between April 1973 and November 1995.
We say: Ajax 1-2 Real Madrid
Ajax must be respected due to the talent that they can call upon, but Madrid have been excellent in recent weeks and we fancy the holders to claim a narrow first-leg advantage.