Novak Djokovic gestures after losing his Men's singles second round match against Uzbekistan's Denis Istomin in Melbourne, Australia on Jan 19, 2017. [Photo/VCG]

Djokovic had won five of the previous six Australian Open championships, and had reached the fourth round or better every year since 2007 — the year before he won his first Grand Slam title at Melbourne Park.

"I'm not used to losing Australian Open second round — I've done so well here."The last time he'd failed to advance beyond the second round at a major was at Wimbledon in 2008.

Rod Laver Arena was not entirely full, with at least one-fifth of the 15,000 seats empty by the fifth set.

Djokovic's usually vocal Serbian fans were also not a presence, with the exception of a couple women waving Serbian flags. Much of the crowd, sensing an upset, was behind Istomin in the fifth set, yelling "Come on Denis!"When Istomin made a backhand winner down the line to break Djokovic to go up 3-2, he let out a roar and the audience stood and roared, too.

Djokovic, meanwhile, looked relatively subdued as the set wore on, hanging his head in between points and walking slowly behind the baseline to prepare to receive serve.

When Djokovic's last ball floated long, the crowd leapt to its feet and cheered as Istomin thrust his arms into the air.

"First of all, I feel sorry for Novak. I was playing so good today," Istomin said. "I surprised myself, as well, today."