MELBOURNE, Australia (AP) -- Novak Djokovic briefly looked vulnerable. Serena Williams just looked lost.
Djokovic, the defending champion, dropped six straight games to Lleyton Hewitt in losing his first set at the Australian Open but kept his composure and won 6-1, 6-3, 4-6, 6-3 late Monday night, ensuring all of the top five men reached the quarterfinals.
"It's obviously the first match that I've been tested,'' the top-seeded Djokovic said. "It was against the player that I expected to be tested.''
Numbers told the story of Williams' stunning 6-2, 6-3 fourth-round loss to Russia's Ekaterina Makarova: seven double-faults, including four in one game; 37 unforced errors, and a first-serve percentage of just over 50 percent had her convinced "maybe I should have started serving lefty.''
Williams 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 here for the first time in 1998, and she hasn't gone out this early since 2006.
"I'm not physically 100 percent, so I can't be so angry at myself, even though I'm very unhappy,'' said Williams, who played on a still-sore left ankle. "I know that I can play a hundred 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 quarterfinals 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 in the quarterfinals on Tuesday.
Kvitova had some trouble late before beating former top-ranked Ana Ivanovic 6-2, 7-6 (2) Monday and will next play Sara Errani of Italy, who beat 2008 semifinalist Zheng Jie 6-2, 6-1.
In the final night match, Djokovic reached the quarterfinals 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 winning the Wimbledon and US 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 quarterfinals where he'll face No. 5 David Ferrer, who had a 6-4, 6-4, 6-1 victory over Richard Gasquet of France.
The loss for former US Open and Wimbledon champion Hewitt ended his 16th 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.''
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 quarterfinals.
"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 quarterfinal since the Open era started in 1968. Shuzo Matsuoka reached the 1995 Wimbledon quarterfinals.
"Feeling unbelievable. My first quarterfinal and beating Tsonga, makes me really happy,'' Nishikori said. "I hope it's big in Japan.''
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.
"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 am feeling so good and so focused. So I played my game, and that's it. I won against Serena. That's amazing.''
Makarova overcame plenty of crowd support for Williams, many of whom weren't that familiar with the Russian. Oracene Price, Williams' mother, was in the players' box with her sunglasses on and a wide-brimmed hat.
In the fourth game of the second set with Makarova serving, Williams netted an easy forehand return. She made an angry sound, and there was a bit of laughter in the crowd. Price just turned away, shaking her head.
After Williams' fourth double-fault in the fifth game of the second set, which gave Makarova the game and a 3-2 lead - Williams shouted "Oh, my God.'' She looked ready to smash her racket, but in the end bounced it on the court and caught it on the rebound.
The 13-time Grand Slam champion had only played two competitive matches since losing the U.S. Open final to Sam Stosur in September, and her light preparation was curtailed when she badly twisted her ankle when she won her second-round match in Brisbane earlier this month.
For that reason, Williams wasn't about to beat herself up over Monday's loss.
"Am I usually angry? I don't know. Crying? I don't cry. So I don't know what I usually project,'' Williams said. "I feel like I didn't play well today. I don't feel like I can't get better.''