Del Potro was just 20 at the time but triumphed in an epic five-set encounter, ending Federer’s run of five consecutive US Open titles.
But the Argentinian has since had two serious wrist injuries and admitted after an almighty comeback against Dominic Thiem in fourth round that fitness would be one of his biggest issues this time around.
Federer too has had his physical problems, struggling with a back injury in the run-up to the US Open and taking medical timeout in his match against Philipp Kohlschreiber.
Here’s how to make sure you don’t miss the action from Arthur Ashe on Wednesday night with stream and TV details.
What time will the Roger Federer v Juan Martin del Potro live stream start?
Assuming the day session on Arthur Ashe does not run late, Roger Federer and Juan Martin del Potro should get on court around 9pm New York time – 2am on Thursday morning in the UK.
However, they will have to watch Madison Keys attempt to make it four American women out of four against Kaia Kanepi of Estonia.
They will start at 7pm in New York (midnight BST) to open an exciting-looking evening session in the Arthur Ashe Stadium.
What TV channel is Roger Federer v Juan Martin del Potro at the US Open 2017 on in the UK?
Tennis coverage in the UK is split between the BBC, Eurosport and Sky Sports.
However, the US Open 2017 will be exclusively live on Eurosport after Sky dropped the tournament after 25 years of sharing the coverage with the channel.
Federer v Del Potro will be featured on Eurosport 1.
How can I watch Roger Federer v Juan Martin del Potro at the US Open 2017 on TV?
Eurosport 1 is available to viewers with a subscription service and the Eurosport package.
The channels are on Sky 412, Virgin Media 524 and BT 413.
How can I stream Roger Federer v Juan Martin del Potro at the US Open 2017 online?
Along with the Eurosport channel live, the online streaming service Eurosport Player will provide coverage of the clash.
You can get a US Open and Vuelta a Espana event pass for £9.99 which gives you full access until the end of September.