The victory made Murray, who won last year with Martina Hingis, the first man to win consecutive U.S. Open mixed doubles titles since Bob Bryan in 2003-04.
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World No. 1 Andy Murray and Evans, who both also exited the singles tournament in round two, were beaten 6-4, 6-3 by Jean-Julien Rojer and Horia Tecau
The defending champions and second seeds lost 6-3 7-6 (7-5) in one hour and 12 minutes on Thursday
The pair were on the backfoot immediately when play finally got underway at 10.42pm local time in Melbourne, as veteran duo Nestor and Stepanek quickly broke twice to take the first set 6-2