Second-seeded Rafael Nadal has 20 Grand Slam titles, while No. 5 seed Stefanos Tsitsipas is seeking his first. The two stars will square off Wednesday at 3:30 a.m. ET in the 2021 Australian Open quarterfinals. Nadal is eyeing a second crown in Melbourne, which would set the record for all-time Grand Slam men's titles, a mark he shares with Roger Federer. Nadal beat the 22-year-old Tsitsipas in the semifinal here in 2019 before losing to Novak Djokovic in the final. The 34-year-old notched his only victory in Melbourne in 2009.

Nadal is a -225 favorite (risk $225 to win $100) in the latest 2021 Australian Open odds from William Hill Sportsbook, with Tsitsipas getting +275 as the underdog (risk $100 to win $275). There are a variety of other Nadal vs. Tsitsipas bets you can make, including an over-under on total games played at 41.5 and who will win the first set (Tsitsipas +134, Nadal -162). Before making any Nadal vs. Tsitsipas picks, be sure to see the 2021 Australian Open predictions from famed tennis handicapper Sean Calvert.

Calvert is the famed handicapper who called Stan Wawrinka winning the 2014 Australian Open at 60-1, the last Australian title won by someone other than Djokovic or Roger Federer. In 2019, Calvert took down a huge score on Dominic Thiem winning Indian Wells at 80-1, among many stunning calls. Anyone following his picks is way up.

Now, Calvert has scrutinized the latest Australian Open 2021 odds and released his coveted best bets. He's sharing all of his picks and analysis at SportsLine.

Rafael Nadal vs. Stefanos Tsitsipas preview

Calvert has seen how Tsitsipas has been hitting serves, but he also knows Nadal still has one of the best return games in tennis. Over the past year, he has won more than 35 percent of his return games and converted almost 47 percent of break points. The back issue that has hampered Nadal in the early rounds seems to be loosening up and he says he is still highly motivated.

Nadal also has one of the game's best forehands and is likely to use that to break down the Greek youngster's one-handed backhand. The speedy surface benefits Nadal, who has not lost to Tsitsipas on a hard court. He is 6-1 in their all-time meetings, losing only on clay in Madrid, and has won 33 straight sets in majors dating to the start of October's French Open.

Tsitsipas ranks fifth in the world, the highest ranking for a Greek player in tennis history. He has five career titles and has made 10 finals since he turned pro in 2016. He has lost just two sets in his first five matches of 2021, both in the five-set, third-round victory against Thanasi Kokkinakis.

The 22-year-old Tsitsipas used an aggressive style to beat Nadal on clay at the Madrid Open in 2019. That could put pressure on the Spaniard's ailing back and force him to make some unforced errors.

How to make Tsitsipas vs. Nadal picks

Is Nadal healthy enough to hold off Tsitsipas? Calvert has released his pick on the winner and has advice on what other 2021 Australian Open picks could pay off in a huge way. Be sure to see Calvert's picks and analysis before locking in your Australian Open 2021 picks for the men's quarterfinals.

Who wins Tsitsipas vs. Nadal in the 2021 Australian Open men's quarterfinal? And what pick could lead to a big return? Visit SportsLine now to see Sean Calvert's best bets for Nadal vs. Tsitsipas, all from the famed tennis handicapper who called Stan Wawrinka winning the 2014 Australian Open at 60-1.