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Drysdale dominated the single scull for over a decade, first having represented New Zealand in 2002 in the men's coxless four, and competed at his first Olympic Games in Athens 2004, finishing fifth in the men's coxless four.
In 2005, he moved to the single sculls, going on to win gold medals at the 2012 London Olympics and the 2016 Rio Games.
He won a bronze medal at the 2008 Beijing Olympics despite being struck down by a serious bout of gastroenteritis.
In 2006, he won the Halberg Supreme Award and was Sportsman of the Year in 2006, 2007, 2009, 2012 and 2016, and in 2009 was made a Member of the New Zealand Order of Merit.
"It has been one hell of a ride! While you always dream of ending it with a fairy tale, time has beaten me on this occasion," Drysdale said on his website.
"I am immensely proud of all I have achieved over the past 21 years. It has not been easy and I've had a lot of ups and downs along the way, but it has all shaped me into the person I am today," he said.
"Tokyo 2020 was supposed to finish 10 months ago along with my rowing career. But with a postponement for 12 months, it was like my body knew the timing and I sustained a reasonably serious back injury, the week I was supposed to be racing at the Olympics.
"With five months away from full training, I thought on a number of occasions my career wasn't going to make it past the end of 2020. But 2021 has been a lot more positive and while I have been hindered at times in the training I could do (to ensure I managed my back), I have been racing against time to try and get myself back to peak form in time to make it back into the team for Tokyo.
"I made good progress and by Nationals in February, followed closely by the trials, I was progressing, but still a long way off where I needed to be.
Unfortunately the cards didn't fall my way, the axing of the men's quad and the subsequent selection of Jordan Parry in the single made my pathway very precarious.
"While it's hard to step away knowing what I could be capable of in 50 days' time, having seen some glimpses of my old self in the last few weeks racing I always knew how hard and improbable the pathway was."
"Since March, I've run my own program, coached myself and had limited support doing it, but to me it has felt like full circle to the beginning of my career, doing it for the love of the sport."
Rowing NZ Chair Gerry Dwyer paid tribute to Drysdale's contribution to rowing.
"Mahé's incredible career, full of phenomenal moments... I remain in awe of his achievements made across the last 20 years.''