Martina Hingis of Switzerland and Jamie Murray of Great Britain
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The number one seeds made short work of the first set, but their opponents, seeded third, battled back.
US Open 2017 highlights: Murray and Hingis win mixed doubles title
The match went to a super tie-break, which Murray and Hingis won 10-8.
It was Murray's fifth Grand Slam title across both doubles disciplines, while it is Hingis's 24th in singles, doubles and mixed doubles.
The top-seeded partnership, who won their first tournament together at Wimbledon in July, pushed their record to an unblemished 10-0 with the win over the number three seeds.
Hingis: If I do play the Australian Open, it will be with Jamie
Hingis, a former world number one singles player who won the US Open title 20 years ago, praised her partner.
"He's a great partner to have. His wingspan as you saw at the end," she said, referring to Murray's reaching overhead smash that ended the tight tie breaker to cap off the hour-long contest.
Bradley Wiggins (Stage 19, 2012)