Sock, Isner and Raonic were the only seeds in action on Wednesday and the trio surprisingly crashed out, denied spots in the quarter-finals.

Top seed and defending champion Sock was the biggest casualty, upstaged by wildcard and fellow American Reilly Opelka 4-6 7-5 6-3 at the ATP 250 tournament.

Sock has endured a disappointing start to the season, with his only win of the year coming at this event, having lost in Auckland and the first round of the Australian Open.

And the world number eight's woes continued, despite claiming the opening set against his unfancied opponent.

Opelka will face Peter Gojowczyk in the quarters after the German eliminated sixth seed Isner.

With only two wins to his name this year, three-time Delray Beach semi-finalist Isner fell to another disappointing defeat, beaten 7-6 (7-3) 6-7 (4-7) 7-6 (7-5).

Gojowczyk will contest his third quarter-final of the year, having already reached the last eight in Doha and Auckland.

Last year's runner-up Raonic was also sent packing following his 6-2 6-4 loss to Steve Johnson.

Raonic – the Canadian ninth seed – tasted defeat against Johnson for the first time in his career as he fell to a 1-3 record for the year.

"I've got to definitely review it, think about it, because that was a pretty poor level I put out there today. Not much to be happy with," he said.

"I think he was just sharp. I've played him before so I knew what to expect. He was more aggressive today than other times. Was that my lack of creation, or was he just taking over and making me feel, in a lot of ways, silly out there? I had a tough time with a lot of things today."

Johnson will face Evgeny Donskoy, who overcame Donald Young 7-6 (8-6) 6-3.