The Swiss champion and has then been dealt a kind second round, facing a qualifier, with Frenchman Gael Monfils, seeded No. 30 at this year’s tournament, potentially in the third round.
If Federer, as expected, is still there a mouth-watering Round of 16 showdown with rising star Stefanos Tsitsipas awaits.
Playing in his first Australian Open main draw, Tsitsipas, seeded 14, begins against Italy’s Matteo Berrettini.
Federer’s seeded quarter-final opponent is No. 6 Marin Cilic, but the Croatian faces a tough route to the final eight and a potential rematch of last year’s final, taking on Bernard Tomic in the opening round and possibly Fernando Verdasco in Round 3.
Brit Andy Murray is also in Federer’s side of the draw, but the former World No. 1 faces a huge ask to make it past the opening round, drawing recently-crowned Doha champion Roberto Bautista Agut, who also beat Novak Djokovic during that run to the title.
At the bottom of the draw, Rafa Nadal starts his quest for a second title against Australian James Duckworth, while teenage sensation Alex de Minaur could be waiting in the third round.
Kyle Edmund is up against former two-time semi-finalist Tomas Berdych, who impressed upon his return to the sport in Doha last week and the other big first round tussle is between American giants John Isner and Reilly Opelka.
Elsewhere, World No. 1 Djokovic starts against a qualifier before a very tough second round match against either Wilfried Tsonga or Martin Klizan, both of whom will present a big challenge. Djokovic could then run into Denis Shapovalov in the third round.
Milos Raonic vs Nick Kyrgios is the big opening round match in the second quarter, along with 2014 champion Stan Wawrinka against Ernests Gulbis.
Dominic Thiem and Borna Coric are the other top seeds in this quarter, which is wide open.
Key first round matches
Nick Kyrgios vs Milos Raonic [16]
Marin Cilic [6] vs Bernard Tomic
Andy Murray vs Roberto Bautista Agut [20]
Grigor Dimitrov [20] vs Janko Tipsarevic
Tomas Berdych vs Kyle Edmund [13]
Top eight seeds
Novak Djokovic [1] vs Qualifier
Rafael Nadal [2] vs James Duckworth [WC]
Roger Federer [3] vs Denis Istomin
Alexander Zverev [4] vs Aljaz Bedene
Kevin Anderson [5] vs Adrian Mannarino
Marin Cilic [6] vs Bernard Tomic
Dominic Thiem [7] vs Benoit Paire
Kei Nishikori [8] vs Qualifier
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