MELBOURNE, Australia - Novak Djokovic showed the first signs of vulnerability at the Australian Open on Monday but still held off Lleyton Hewitt to reach the quarter-finals.

American Serena Williams can't say the same in the women's event, though.

Djokovic, the defending men's champion, held his composure to defeat Hewitt 6-1, 6-3, 4-6, 6-3 to ensure the top five men reached the quarter-finals.

"It's obviously the first match that I've been tested," Djokovic said. "It was against the player that I expected to be tested."

Hewitt advanced to the meeting with Djokovic after beating Canadian Milos Raonic in third-round action.

Numbers told the surprising story for Williams in her fourth-round loss. She had seven double-faults, including four in one game; 37 unforced errors, and a first-serve percentage of just over 50 per cent had her convinced "maybe I should have started serving lefty."

Some other numbers indicated why her 6-2, 6-3 loss to Ekaterina Makarova of Russia on what she admitted was a still-sore left ankle was more of a shock.

She has played 43 singles matches at Melbourne Park since she won the first of her five Australian Open titles in 2003, and Monday's loss was just her third. She's 54-7 since playing at the Australian Open for the first time in 1998, and she hasn't gone out this early since 2006.

"I'm not physically 100 per cent, so I can't be so angry at myself, even though I'm very unhappy," Williams said. "I know that I can play 100 times better than I did this whole tournament."

Without Williams, who injured her left ankle in Brisbane two weeks ago, the only major winners still in contention were Maria Sharapova, defending champion Kim Clijsters and Wimbledon winner Petra Kvitova.

Sharapova earned the right to play Makarova in the quarter-finals when she beat Sabine Lisicki of Germany 3-6, 6-2, 6-3 in a night match. The 2008 champion blew a 3-0 lead in the opening set, needed three set points to win the second and advanced on her second match point despite making 47 unforced errors and eight double-faults.

"A lot of ups and downs today -- fortunately I finished on a high note," she said. "Even though I didn't play my best tennis I fought to the end and sometimes that's what gets you through."

Top-seeded Caroline Wozniacki, still in search of her first Grand Slam title, was to play Clijsters on Tuesday.

Kvitova had some trouble late before beating former top-ranked Ana Ivanovic 6-2, 7-6 (2) on Monday and will next play Sara Errani of Italy, who beat 2008 semifinalist Zheng Jie 6-2, 6-1.

In the late-finishing night match, Djokovic reached the quarter-finals for the fifth straight year with the win over Hewitt, ending Australia's participation in the singles draws.

"Lleyton was playing in front of his crowd. Obviously, he loves competing against the top guys on the big stage, and he proved it again," Djokovic said.

Djokovic is aiming to become only the fifth man in the Open era to win three consecutive majors after collecting the Wimbledon and U.S. Open titles last year.

Nobody had taken more than three games in a set off Djokovic in the opening three rounds. He was leading by two sets and a break before Hewitt, who was playing on a wild-card entry after his ranking plummeted in an injury-plagued 2011, ended that streak by winning six straight games to force a fourth set.

But Djokovic regained his cool, cut out the loose shots and advanced to the quarter-finals against No. 5 David Ferrer, who had a 6-4, 6-4, 6-1 victory over Richard Gasquet of France.

The loss for former U.S. Open and Wimbledon champion Hewitt ended his 16th campaign at the Australian Open.

"I have to give credit to ... Lleyton, who never gives up," Djokovic said. "He's a great competitor and he obviously made me play an extra shot, I made couple of unforced errors and I got him back to the match. He's very well known for that.

"For two sets and 3-0 I was playing really well and suddenly I stopped moving."

Earlier, two-time runner-up Andy Murray was leading 6-1, 6-1, 1-0 when Mikhail Kukushkin retired from their fourth-round match with a left hip injury, giving Murray an easy path into the quarter-finals.

"It's obviously good for me, I get to conserve some energy," Murray said. "Tough for him, first time in the fourth-round of a Slam."

Murray will next play Kei Nishikori, who had a 2-6, 6-2, 6-1, 3-6, 6-3 win over sixth-seeded Jo-Wilfried Tsonga, the 2008 finalist.

The 22-year-old Nishikori became the first Japanese man in the last eight at the Australian Open in 80 years, and only the second man from his country to reach a Grand Slam quarter-final since the Open era started in 1968. Shuzo Matsuoka reached the 1995 Wimbledon quarter-finals.

"Is feeling unbelievable. My first quarter-final and beating Tsonga, makes me really happy," Nishikori said. "I hope it's big in Japan.

"A lot of people messaged me a couple of days ago about the round of 16 and now the quarter-finals. It's really exciting."

Makarova, a 23-year-old Russian left-hander, was equally thrilled about her win over Williams. And considering she had lost in the first round of the last six tournaments she played, in awe over who she beat.

"Yeah, I'm surprised because she's a great player and it's really tough to play against her," Makarova said. "But, I don't know, I just feeling so good and so focus.

"So I played my game, and that's it. I won against Serena. That's amazing."