Van Persie opened the campaign with seven goals in 11 Barclays Premier League games but damaged ankle ligaments playing for Holland in November and has not featured since.
Gunning for glory: Arsenal's Robin van Persie is set to return to action after five months out
Wenger said: 'The biggest frustration was because he had started to compete as one of the best players in the world and suddenly he was out. I am convinced you would have talked about Van Persie alongside Messi, Ronaldo and Rooney. I am sure.
'He is a very important player for this club, very important for our confidence and our offensive power. He can give a final ball, score goals and is good on set-pieces.
'He is also a leader because he has a football brain and is a football thinker. He is a winner and he has matured a lot in the last three or four years.
'The sadness was that we lost him very early in the season.
'Nobody knows what difference he might have made. You have always that thought at the end of the season. You think, 'What if you had one or two more points or if we had those points at Birmingham?'
VIDEO: Wenger on Van Persie return.'But you forget as well that you won games in the last seconds or minutes.'
Wenger must cope without Alex Song against Tottenham, while Aaron Lennon, who has not played for Spurs since December, is missing once again despite returning to training last week.
Asked whether Lennon would be fit for the World Cup, Tottenham boss Harry Redknapp said: 'Hopefully, although I hope he's fit to play for Tottenham first and foremost.'
Redknapp is pondering whether to include skipper Ledley King, but Vedran Corluka and Niko Kranjcar are out with ankle injuries and Wilson Palacios is suspended.
Redknapp believes the game is key in the race for fourth. He said: 'If we can get a win we've still got a chance.'
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