Rafael Nadal was dumped out of the Miami Open on Sunday as he suffered a shock defeat to fellow Spaniard Fernando Verdasco.
The second seed is a four-time finalist in Florida but has never won the tournament and will have to wait at least another year after going down 6-4 2-6 6-3 to his countryman.
Nadal fought back well after losing the first set and looked to have all the momentum but was broken to go 3-1 down in the third and Verdasco held his nerve to move into the last-16.
British third seed Andy Murray cruised to a 6-3 6-4 victory over Santiago Giraldo with the minimum of fuss.
Murray continued the commanding form he displayed in seeing off Donald Young on Friday and his Colombian opponent, seeded 27th, had no answer.
There were, however, shock defeats for seventh seed Stan Wawrinka and Jo-Wilfried Tsonga, seeded 11th and playing in his first competition this year.
Wawrinka was edged out by Adrian Mannarino 7-6 (7/4) 7-6 (7/5), while Tsonga was sent packing after a 6-4 7-6 (7/4) defeat to French compatriot Gael Monfils.
Fifteenth seed Kevin Anderson beat Leonardo Mayer 6-4 6-4 while Austria's Dominic Thiem came through 6-4 6-3 against Jack Sock of the United States.
In the women's draw, Serena Williams ruthlessly ended the challenge of 15-year-old wildcard CiCi Bellis to ease into the fourth round.
Williams, ranked number one in the world, was taking on the game's junior number one in a clash of generations, and unsurprisingly it was the top seed who came through against her fellow American.
The 33-year-old triumphed 6-1 6-1 to set up a last-16 clash against former two-time grand slam champion Svetlana Kuznetsova, who ended the challenge of 13th seed Angelique Kerber 6-3 3-6 6-3.
Third seed Simona Halep was a 6-4 7-5 winner over Camila Giorgi, but the 30th seed's Italian compatriots fared better.
Fifteenth seed Flavia Pennetta defeated former world number one Victoria Azarenka 7-5 7-6 (8/6) and Sara Errani, seeded 11th, booked her spot in the last 16 after hitting back to oust Garbine Muguruza 4-6 6-4 6-1.
Elsewhere, Switzerand's Belinda Bencic knocked out German qualifier Tatjana Maria 6-4 7-5 and Sloane Stephens was a 6-4 6-4 winner over Johanna Larsson.
In the day's later matches, Sabine Lisicki beat Ana Ivanovic 7-6 (7/4) 7-5 while back in the men's draw, Tomas Berdych was a 6-7 (4/7) 7-6 (7/3) 6-1 winner against Bernard Tomic and Juan Monaco beat Guillermo Garcia-Lopez 7-5 6-4.