McLaren's Fernando Alonso will miss this year's Monaco Grand Prix to race in the Indianapolis 500.
The double world champion has been granted full approval and support by McLaren and engine partner Honda.
Alonso, 35, will race for the Honda-powered Andretti team on 28 May.
McLaren are yet to decide who will replace him in Monaco, but the Spaniard's absence for round six of the Formula One Championship raises the possibility that Jenson Button, who remains under contract in an ambassadorial role for Mclaren, could return for the Monte Carlo race.
Alonso expressed his delight to be taking part in next month's Indy 500.
“I’m immensely excited that I’ll be racing in this year’s Indy 500, with McLaren, Honda and Andretti Autosport," he said.
“The Indy 500 is one of the most famous races on the global motorsport calendar, rivalled only by the Le Mans 24 Hours and the Monaco Grand Prix [which Fernando has won twice, one of those victories at the wheel of a McLaren (in 2007)], and it’s of course a regret of mine that I won’t be able to race at Monaco this year.
"But Monaco will be the only 2017 Grand Prix I’ll be missing, and I’ll be back in the cockpit of the McLaren-Honda MCL32 for the Canadian Grand Prix in Montreal in early June."
Alonso said he is bidding to win the so-called 'triple crown' of Monaco, the Indy 500 and Le Mans. Only one man has won all three in his career - the late Graham Hill in the 1960s.
"It's a tough challenge, but I'm up for it. I don't know when I'm going to race at Le Mans, but one day I intend to. I'm only 35. I've got plenty of time for that."
Having never driven an IndyCar on a super-speedway before, Alonso admits he faces a "steep learning curve" but remains confident he cam "get to grips with it fast".
“I’ve never raced an IndyCar car before, and neither have I ever driven on a super-speedway, but I’m confident that I’ll get to grips with it fast. I’ve watched a lot of IndyCar action on TV and online, and it’s clear that great precision is required to race in close proximity with other cars on the far side of 220mph [354km/h].
"I realise I’ll be on a steep learning curve, but I’ll be flying to Indianapolis from Barcelona immediately after the Spanish Grand Prix, practising our McLaren-Honda-Andretti car at Indy from May 15th onwards, hopefully clocking up a large number of miles every day, and I know how good the Andretti Autosport guys are.
"I’ll be proud to race with them, and I intend to mine their knowledge and expertise for as much info as I possibly can."
McLaren executive director Zak Brown stopped short of saying Alonso could win the event but warned against dismissing the Spaniard.
He said: "Could Fernando win this year's Indy 500? Well, I wouldn't be so silly as to make any such rash prediction, but I expect him to be in the mix.
"Put it this way: the team he'll be racing for won the race last year, using the same Honda engine, and he's the best racing driver in the world. That's quite a compelling combination."
The unexpected development marks the first time in 38 years that McLaren has featured in the Indy 500. They won the race with their own car in 1974 and 1976.
The Indy 500 is the most prestigious race in the USA and is the blue riband event of the IndyCar Series.
It's hoped Alonso's participation in the race will encourage him to re-sign at McLaren, with his current contract set to expire at the end of the season.