He lost to Tobias Kamke in a rain-interrupted second-round encounter in Miami.
The world number seven, playing in his first match at this year's tournament after being handed a first-round bye, crumbled after failing to convert two set points at 5-2 in the first set.
The German dominated the second set when play resumed following the weather delay and ran out a 7-6 (7/5) 6-1 winner to reach round three of a Masters 1000 event for the first time in his career.
"I saved two set points at 5 2 and somehow I came back in that set and had the chance to win it," Kamke said on www.atpworldtour.com after eliminating last weekend's Indian Wells runner-up.
"The second set, after the break, I felt even better. Then in the beginning, he missed some easy forehands and he was a little bit frustrated, I think.
"He didn't play obviously his best tennis, but still I think I did a good job and pretty satisfied with that."
World number one Novak Djokovic enjoyed a straightforward route into round three - after taking to the court later than expected due to a three-hour rain delay and 27-minute power cut.
He took just 53 minutes to hammer Czech Lukas Rosol 6-1 6-0.
"It is a great start," the Serbian top seed said. "After Indian Wells, I tried to rest. There are different conditions here, but Friday was perfect for tennis. I enjoyed every moment of it and I love this court."
Third seed Ferrer advanced to the third round without having to set foot on court as his Russian opponent Dmitry Tursunov withdrew due to a stomach bug.
Ferrer will next face Fabio Fognini after the 32nd seed from Italy toppled Frenchman Michael Llodra 6-4 6-1.
Ferrer's fellow Spaniard Albert Ramos also advanced, upsetting 12th-seeded Argentinian Juan Monaco 6-2 4-6 6-3.
Seventh-seeded Serbian (7) Janko Tipsarevic (Ser) beat Dudi Sela (Isr) 6-2 6-4, while 11th seed Gilles Simon ended Lleyton Hewitt's run by defeating the Australian 6-3 6-3.
James Blake had six breaks of serve en route to seeing off 24th seed Julien Benneteau in just over an hour.
He was not the only seeded casualty in the men's draw, with Jeremy Chardy (22), Florian Mayer (23) and Marcel Granollers (31) also crashing out - at the hands of Xavier Malisse, Grega Zemlja and Jurgen Melzer, respectively.
Thirteenth seed Kei Nishikori did advance, though - as did Tommy Haas (15), Alexandr Dolgopolov (19), Kevin Anderson (26) and Somdev Devvarman.
In the women's event, Lauren Davis made the most of her 'lucky loser' status by beating fellow American Madison Keys 6-1 5-7 7-6 (9/7). Davis was handed a place in the draw after second seed Victoria Azarenka of Belarus withdrew citing an ankle injury.
Third seed Maria Sharapova needed less than an hour to crush wild card Eugenie Bouchard 6-2 6-0, with sixth seed Angelique Kerber made to work much harder to get past Francesca Schiavone 6-7 (5/7) 6-3 6-2.
Ekaterina Makarova and Tamira Paszek were the only women's seeds to fall on Friday.
Svetlana Kuznetsova sank 18th seed Makarova 6-4 6-4 in an all-Russian encounter, while Romania's Simona Halep ousted 26th seed Paszek 6-1 6-7 (4/7) 7-5.
Serbian duo Ana Ivanovic and Jelena Jankovic posted straight-sets wins over Urszula Radwanska and Victoria Duval, while eighth seed Sara Errani overcame Daniela Hantuchova 6-3 6-1 and 11th seed Nadia Petrova saw off Jie Zheng - also 6-3 6-1.
There were also victories for Maria Kirilenko, Roberta Vinci, Carla Suarez-Navarro, Klara Zakopalova, Sorana Cirstea, Elena Vesnina and Alize Cornet.