Deputy Chief Medical Officer Dr Ronan Glynn has resigned, the Department of Health has confirmed.
He is expected to leave his post at the end of the month and take up a role with consultancy firm EY later this year.
Dr Glynn qualified as a physiotherapist in 2002 and a medical doctor in 2007.
He completed his laboratory based PhD in surgical oncology in 2012 and achieved a Masters in Public Health in 2015.
In October 2018, he was appointed Deputy Chief Medical Officer at the Department of Health.
In July 2020, Dr Glynn became Acting Chief Medical Officer, when the CMO Dr Tony Holohan stood aside due to his late wife's illness.
As part of that temporary role, he also became Chair of the National Public Health Emergency Team.
He participated in the Covid-19 press briefings at the Department of Health and both he and Dr Holohan regularly briefed the Cabinet Committee on Covid-19 at Government Buildings.
Today's announcement comes ahead of the scheduled departure of Dr Holohan in July, following controversy over his planned secondment to Trinity College Dublin.
The Department of Health has said it is anticipated that the role of Chief Medical Officer will be advertised shortly.
It said it will be filled by open competition under the auspices of the Public Appointments Service and the Top-Level Appointments Committee (TLAC).
Govt leaders offer well wishes
In a statement this afternoon, Taoiseach Micheál Martin said he wanted to thank Dr Glynn for "his outstanding service to the Irish people".
He added: "I worked very well with Ronan throughout the pandemic, and his unstinting, dedicated and tireless work in fighting Covid-19 was so important to the health and well-being of the nation.
"Ronan's calm demeanour and knowledge of Public Health played a significant role in our national effort throughout the pandemic.
"Ronan personifies the very best of Irish public service, and I wish him well in the future."
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Tánaiste Leo Varadkar has said that he respects Dr Glynn's decision to leave and wishes him the best in his new role.
Speaking on RTÉ's News at One, Mr Varadkar thanked both Dr Holohan and Dr Glynn for their contribution to public health.
"They're two people who have provided enormous service to the public. (I) want to thank them again, for the contribution that they've made.
"These are very much personal decisions. After a number of very busy, very intense years, they've decided to move on. We respect that and wish them the best in their new roles," he said.
Mr Varadkar added that the two positions will be now advertised and "it'll be open to other public health doctors or indeed other people appropriately qualified to apply for the jobs".
Minister for Health Stephen Donnelly said he wished Dr Glynn all the best in the next chapter of his career.
"Throughout the pandemic, he advised me as both ACMO and DCMO. His knowledge and advice was vital in our national response," the Minister said.
Mr Donnelly said Dr Glynn always showed tremendous commitment to protecting public health and he thanked him for his "unwavering dedication during his time in the Department".
Social Democrats co-leader Róisín Shortall said it was a huge loss to the public system that two of the people who chiefly led the response to Covid had now resigned.
Additional reporting Fergal Bowers