Djokovic has been the form player on the men's tour in 2008
Novak Djokovic suffered a shock defeat by South African qualifier Kevin Anderson at the Sony Ericsson Open.
Defending champion Djokovic arrived in Miami as the form player having won in Indian Wells last week but lost 7-6 (7-1) 3-6 6-4 to the world number 122.
The third seed, who had a first-round bye, was broken twice in the deciding set and Anderson served out to win.
In other matches, Rafael Nadal, Justine Henin, Serena and Venus Williams and Svetlana Kuznetsova all made progress.
Djokovic, 20 has been the star of the ATP Tour so far in 2008, having won his first Grand Slam title in Australia and added the Masters Series crown in Indian Wells.
The good thing about this loss is that I can get a bit of a longer period of preparation and vacation
In contrast, the 6ft 7in Anderson only turned professional last year despite being 21, although he reached the final in Las Vegas earlier this year.
Anderson was roared on by plenty of supporters in the crowd having come through the American college system.
The South African took the first set by dominating the tie-break but Djokovic looked set to get out of trouble when he levelled in the second and went 2-0 up in the decider.
But the Serb appeared rattled by a time violation warning while preparing to serve at deuce, lost 13 points in a row and found himself a break down.
"Obviously the time violation and a lot of different things affected my service game," said Djokovic.
"I didn't focus myself in that moment. But, you know, that's OK. It's all part of the game."
Anderson took full advantage, converting his third match point for a sensational victory.
"I kept telling myself, 'I can do this. I've just got to believe in myself,'" said Anderson.
"Even still, just knowing what he's done and what a great player he is, to have beaten him is a tremendous experience for me."
Djokovic immediately looked on the bright side of the unexpectedly long break he now has.
"The good thing about this loss is that I can get a bit of a longer period of preparation and vacation as well," he said.
World number two Nadal overcame stubborn early resistance from Germany's Benjamin Becker to win 7-5 6-2.
In the women's event, Belgium's Henin was playing for the first time since defeat by Francesca Schiavone in Dubai last month, and saw off Germany's Angelique Kerber 6-4 6-2.
"I feel much better physically today than I did a few weeks ago - that's for sure," said Henin, who has struggled with a knee injury.
"So we could see it in my serve, I can play with my forehand again and I feel that everything is better now."
Serena Williams thrashed Edina Gallovits 6-1 6-2, while third seed Kuznetsova beat Yung-Jan Chan 6-1 3-6 6-0.
"I love playing here," said Williams, who lives nearby in Palm Beach Gardens.
"I love having all my friends come and see me play. It's like playing at home."
Her sister Venus, the sixth seed, defeated Poland's Marta Domachowska 6-4 6-3.