Fifth seed and Wimbledon runner-up Milos Raonic of Canada was knocked out of the US Open on Wednesday by American qualifier Ryan Harrison.

The 120th-ranked Harrison won 6-7 (4/7), 7-5, 7-5, 6-1 and goes on to face Marcos Baghdatis for a place in the last 16. 

"It was extremely physical out there but I was playing on adrenaline," said 24-year-old Harrison who was as high as 43 in the world in 2012.

"This is a big win for me. I have been playing well all summer."

Raonic, considered as a potential title dangerman in New York, hit 18 aces and 69 winners but committed 62 unforced errors.

Harrison has now reached the third round of a Slam for the first time after recording just a second win over a top 10 opponent in 27 meetings.

Mikhail Youzhny (RUS) bt Guido Pella (ARG) 6-2, 6-1, 7-6 (7/3)

John Isner (USA x20) bt Steve Darcis (BEL) 6-3, 6-4, 6-7 (10/12), 6-3

Kyle Edmund (GBR) bt Ernesto Escobedo (USA) 7-5, 6-4, 6-4

Jo-Wilfried Tsonga (FRA x9) bt James Duckworth (AUS) 6-4, 3-6, 6-3, 6-4

Kevin Anderson (RSA x23) bt Vasek Pospisil (CAN) 7-6 (7/3), 6-4, 6-4

Jack Sock (USA x26) bt Mischa Zverev (GER) 6-1, 6-1, 6-2

Marin Cilic (CRO x7) bt Sergiy Stakhovsky (UKR) 6-1, 6-2, 6-3

Andrey Kuznetsov (RUS) bt Albert Ramos (ESP x31) 7-5, 6-4, 7-6 (7/5)

Gael Monfils (FRA x10) bt Jan Sátral (CZE) 7-5, 6-4, 6-3

Nicolas Almagro (ESP) bt Pablo Cuevas (URU x18) 7-6 (7/5), 6-4, 7-6 (11/9)

Marcos Baghdatis (CYP) bt Benoît Paire (FRA x32) 6-2, 6-4, 3-6, 6-4