Champions League debutants Villarreal are hoping to complete a memorable double and dispose of Rangers in the same way as they dealt with the Glasgow club's city rivals Celtic two years ago.
Villarreal beat Celtic 2-0 at the Madrigal after a 1-1 draw in Scotland to reach the semi-finals of the UEFA Cup in their first season in European competition in 2004 and were only denied a place in the final by regional rivals and eventual winners Valencia.
After their 2-2 draw at Ibrox two weeks ago, the Spaniards hold the edge once again and the statistics point towards another famous victory on Tuesday.
Villarreal are unbeaten in the Champions League this season and have kept a clean sheet in 13 of the 16 games they have played at home in Europe, conceding a mere four goals in total.
Rangers, on the other hand, have only managed to win three of their last 21 previous away games in the Champions League and have never recorded a victory on Spanish soil in Europe.
Villarreal warmed up for the second leg of their first knockout round tie with a 3-2 comeback win over struggling Alaves at the weekend, with playmaker Juan Roman Riquelme again in inspirational form.
The Argentine international, who has been Villarreal's most influential player in the last three seasons, ran the show in midfield and scored twice to cancel out Alaves goals before Mexico striker Guillermo Franco grabbed the winner.
Argentine-born Franco, who joined Villarreal from Monterrey in January, turned in an impressive display on his debut at the Madrigal and his prowess in the air may have earned him a place in the starting line-up for Tuesday's match.
With another of the club's Argentine brigade Juan Pablo Sorin doubtful after picking up a calf injury on international duty, the experienced Italian midfielder Alessio Tacchinardi is likely to partner Marcos Senna in the centre of midfield.
Brazilian-born Senna, who made a promising debut for Spain in their 3-2 victory over Ivory Coast last week, is confident his side can complete the task against Rangers.
"The victory against Alaves has given us a lot of confidence for the Rangers match and we won't be feeling any after-effects because we are so motivated. We got a good result in Glasgow and now we need to finish the job at the Madrigal."
Rangers, who beat Falkirk in the SPL at the weekend, are battling to contain a 'flu virus ahead of Tuesday's match.
They missed defender Ian Murray for the Falkirk game while midfielder Chris Burke managed just 45 minutes due to the effects of the virus. Both players had been sent home from training last week.
"I hope it doesn't spread any further or we have real problems," manager Alex McLeish told BBC Radio Scotland before saying that two more players were also suffering from 'flu.
Rangers also had to contend with injuries to Belgian Thomas Buffel, Danish forward Peter Lovenkrands and Tunisian midfielder Hamed Namouchi.
"We have a favourable chance of having Thomas and Peter available but Hamed is more of a doubt," McLeish told reporters. "He came back from international duty with an injury to his knee."
Rangers will also be without suspended Croatian striker Dado Prso who picked up a third yellow card in the first leg at Ibrox.
Villarreal: 13-Sebastian Viera; 17-Javi Venta, 2-Gonzalo Rodriguez, 16-Quique Alvarez, 3-Rodolfo Arruabarrena; 14-Hector Font or 6-Josico, 19-Marcos Senna, 18-Alessio Tacchinardi or 12-Juan Pablo Sorin, 8-Juan Roman Riquelme, 5-Diego Forlan, 99-Guillermo Franco
Rangers: 25 -Ronald Waterreus; 20-Alan Hutton, 14-Sotirios Kyrgiakos, 34-Steven Smith, 16-Julien Rodriguez; 6-Barry Ferguson, 7-Brahim Hemdani, 17-Chris Burke; 4-Thomas Buffel, 26-Peter Lovenkrands, 27-Kris Boyd
Referee: Alain Hamer (Luxembourg)
(Additional reporting by Kenny McDonald)