Cristiano Ronaldo was ruled out of the match after picking up an ankle injury playing for Real Madrid on Sunday and although he failed to live up to his price tag at the World Cup, Portugal will miss him, especially after Simao unexpectedly quit the side last week.
Coach Carlos Queiroz is set to miss the first four qualifiers after his one-month ban from the Portuguese Football Federation's (FPF) for insulting anti-doping doctors before the World Cup was upped to six by the country's anti-doping agency.
Queiroz has said he will appeal the decision but the incident could lead to him losing his job.
"(The ban) will not affect the players' performances, the squad will not be affected," said FPF chief Gilberto Madail.
"The players have a lot of experience and can play in auto-pilot mode," he added.
But despite these assurances, assistant Agostinho Oliveira will have to guide a squad that due to several injuries and retirements is much changed from the one that lost to Spain in the second round of the World Cup in South Africa.
To fill the void left by Ronaldo and Simao, Portugal will hope Nani can rebound from the disappointment of missing out on the World Cup through injury.
Ricardo Quaresma, called up after Ronaldo's injury, will want to show his revival at Besiktas after a dismal spell at Inter Milan can also benefit the national side.
In defence, dependable right back Paulo Ferreira has retired from international football, making way for a debut call up for Braga's Silvio.
Holding midfielders Pepe and Pedro Mendes are injured and the vacancy is set to be filled by Valencia's Manuel Fernandes.
Playmaker Deco has also quit the side, but in Tiago Portugal have a replacement who showed he is up to the job by impressing in South Africa.
The dynamic and tactically astute Raul Meireles has arguably been Portugal's best performer for the last two years, but he may start on the bench against Cyprus after barely playing for Porto in the pre-season before moving to Liverpool last week.
The man who replaced him seamlessly at Porto, former Sporting captain Joao Moutinho, has been rewarded with a return to the national squad after showing mediocre form last season.
Despite Queiroz's ban, the injuries and the retirements, anything other than a win against Cyprus would be a major upset for Portugal and bring back bad memories of the weak start to the last World Cup qualifying campaign.
The Cypriots, 63rd in the FIFA ranking, are unlikely to threaten a maiden win against the Portuguese, with the match in Norway four days later likely to prove a much more stern test.
Probable teams:
Portugal: Eduardo; Miguel, Ricardo Carvalho, Bruno Alves, Fabio Coentrao; Manuel Fernandes, Tiago, Moutinho; Nani, Liedson, Quaresma.
Cyprus: Antonis Georgallides; Savvas Poursaitides, Sinica Dobrasinovic, Paraskevas Christou, Elias Charalambous; Constantinos Charalambides, Christakis Marangos, Constantinos Makrid
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