Playing in their fourth US Open together, Ram and Salisbury have enjoyed plenty of success at Flushing Meadows.
They reached the semi-finals in 2020 before claiming back-to-back titles on the Arthur Ashe Stadium court to join the Australian duo of Todd Woodbridge and Mark Woodforde in 1995-96 as the only pair in the Open era to stage a successful defence.
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"It's pretty crazy. I can't quite believe we're standing here again," said Salisbury, who retains his ranking as the world's number one doubles player with the win.
"It is so, so special to be playing in this incredible stadium and to have that piece of history as well to have won this twice in a row is amazing."
As expected, a final pitting number one seeds Ram and Salisbury against number two pairing Dutchman Koolhof and Briton Skupski was a tight affair from start to finish.
A tense first set produced a single break chance going to Ram and Salisbury, who were unable to convert as the opener ended in a stalemate and tiebreak.
The first opening set to go to a tie break in the men's doubles final since 2010 looked set to go to Koolhof and Skupski, who charged ahead 4-1, but Ram and Salisbury swept the next six points to snatch a one-set lead.
Koolhof and Skupski, who formed a new partnership this year, secured the first break of the contest to go 2-1 up in the second but Ram and Salisbury immediately answered with a break of their own to get back on serve.
The set appeared headed for another tie break until Ram and Salisbury brought the contest to a sudden end, breaking Koolhof and Skupski again to seal victory on the first match point.
"I got to come here the first year this stadium opened. I watched (Pete) Sampras win this tournament, I watched Andy Roddick win this tournament, Venus and Serena," said Ram.
"To be a small part of that as an American I don't even know what to say," he added.
Sampras won the singles title five times while Roddick won the trophy once. Venus and Serena won the doubles title twice and were also multiple winners of the singles crown.
