The Serbian world number one and his Swiss opponent have won eight of the nine titles on the Rod Laver Arena since 2010, and 11 of the last 13 on the bright blue courts in central Melbourne.
Caroline Wozniacki of Denmark plays a forehand during her first round match against Laura Siegemund of Germany at the ASB Classic on January 02, 2019 in Auckland, New Zealand.
Williams enters the year's first grand slam ranked 16th, but she still remains the favourite in Melbourne even if she lost to Naomi Osaka in the Flushing Meadows final.
Williams missed the chance to equal the record in both the Wimbledon and US Open finals last season and says she is now avoiding focusing on the numbers.
Serena Williams hopes that his Australian Open will allow her to match Margaret Court's record of 24 Grand Slam titles.
The shock diagnosis came after Wozniacki had returned to number one and taken her WTA tour title tally to 30 with victories not only in Melbourne, but also Eastbourne and Beijing.
It was her 23rd Grand Slam championship.
Williams is also playing in her first Australian Open since winning it in 2017.
Men's top seed Djokovic, who was defending his title when he lost to Istomin, will first meet a qualifier in his bid for a record seventh Melbourne title and third Grand Slam crown in succession following wins at Wimbledon and the U.S. Open.
Defending champion Caroline Wozniacki, who claimed her first major title by beating Halep in the final of the Australian Open a year ago, will start the defence of her title against Alison Van Uytvanck of Belgium.
If US Open victor Naomi Osaka is feeling the pressure of being the tennis world's newest Grand Slam champion, she's hiding it well in the lead-up to the Australian Open.
Osaka suffered a straight-sets loss to Lesia Tsurenko in the semi-final of the Brisbane International and withdrew from the Sydney International in frustration.
Yet she appears to have put the emotional turmoil experienced in NY behind her and is revelling in her status as standard bearer for the next generation of women's players.
"I feel like if there's one thing I should be able to do it's draw a tennis ball", the Olympic gold medalist, 37, explained.
"I always have insane big goals but I like to keep them to myself".
"I think that sometimes we've gone too far", Bernard Giudicelli told a tennis magazine as the federation pledged to introduce a dress code for this year's tournament in Paris.