The European neighbours have not met since that pulsating 3-3 draw in the group stage of the 2018 World Cup, with a proposed friendly in June called off amid the coronavirus crisis.
Portugal began their defence of their UEFA Nations League crown in perfect fashion with dominant victories over Croatia and Sweden in Group A3 last month, and Fernando Santos must now navigate his side through another challenging fixture against the latter after a showdown with France this weekend.
For now, though, Portugal will want to gain the bragging rights over Spain as they meet their fellow powerhouses in a friendly for the first time since 2010, with the Nations League holders marching to a 4-0 victory in that encounter.
The reigning European Champions only suffered one defeat en route to the group stages of next year's European Championships - a 2-1 loss against Ukraine - which was the first time that Portugal had come out on the wrong end of the scoreline since being knocked out of the World Cup by Uruguay two years ago.
Portugal are undefeated in their last five friendly matches, with their most recent exhibition game ending in a 3-1 victory over Scotland in October 2018, and Santos has guided his men to nine wins from their last 10 in all competitions.
Meanwhile, Spain's also find themselves top of their Nations League group following a 1-1 draw with Germany and a crushing 4-0 victory over Ukraine in September's fixtures, with Luis Enrique's side on course to qualify for the finals after finishing one point behind England in the 2018-19 edition.
As is the case with Portugal, the three-time European champions also qualified for next summer's tournament with no trouble whatsoever, finishing top of the pile in Group F having won eight and drawn two of their ten qualifying matches.
Enrique's side will be taking on Switzerland and Ukraine in the days following their friendly showdown with Portugal, and Spain are unbeaten in all competitions since suffering back-to-back 3-2 defeats in the 2018-19 Nations League against England and Croatia.
The 2010 World Cup champions have not tasted defeat in an exhibition match since that shock 1-0 defeat to Georgia in June 2016, with Spain searching for their fourth friendly victory in a row following wins over Tunisia, Wales and Bosnia-Herzegovina in 2018.
Portugal International Friendlies form: LDDWDW
Portugal form (all competitions): WLWWWW
Spain International Friendlies form: DWDWWW
Spain form (all competitions): DDWWDW
Both managers will want to avoid any injury layoffs before the real challenges begin in the Nations League, and that is likely to factor into team selection.
Cristiano Ronaldo's hat-trick in the six-goal thriller at the 2018 World Cup means that he is tied with Spain's Telmo Zarra for goals in this fixture, with Zarra's compatriot Isidro Langara leading the way with seven strikes against Portugal.
Barcelona's Jordi Alba suffered an injury in La Blaugrana's draw with Sevilla but was overlooked by Enrique anyway, while on the opposite side of defence, Dani Carvajal has been forced to withdraw after suffering a knee injury.
Teenage sensation Ansu Fati has enjoyed a stellar start to the new La Liga campaign with Barcelona, banking three goals and one assist from three games in the 2020-21 campaign, and the 17-year-old will be looking to build on his first international goal against Ukraine which made him Spain's youngest-ever goalscorer.
Portugal possible starting lineup:
Lopes; N. Semedo, Dias, Pepe, Sequeira; Carvalho, Moutinho, Fernandes; Podence, Felix, Jota
Spain possible starting lineup:
De Gea; Roberto, Ramos, Torres, Reguilon; Busquets, Ceballos, Merino; Traore, Rodrigo, Fati
We say: Portugal 1-1 Spain
With the upcoming Nations League fixtures obviously taking priority for Portugal and Spain, both sides may be tempted to err on the side of caution for this encounter, and a number of up-and-coming players will be hoping to get some minutes on the board here. Wednesday's clash is poised to be a closely-fought battle, which we are tipping to end in a 1-1 stalemate.