Six Nations champions Wales will tackle New Zealand and South Africa as part of a four-Test autumn schedule later this year.
The Welsh Rugby Union has also announced Tests against Australia and Fiji for Wayne Pivac's team.
All the games are scheduled at Cardiff's Principality Stadium, with the series opening against New Zealand on 30 October.
The Springboks follow a week later, then Fiji on Sunday 14 November, followed by Australia's visit on 20 November.
Ireland are due to play New Zealand, Argentina and a tier 2 nation in the autumn but these fixtures have not yet been confirmed.
WRU chief executive Steve Phillips said: "It is our aim and ambition to deliver the Autumn Nations Series 2021 with full crowds.
"We are working alongside Welsh Government and Public Health Wales to ensure this is done correctly and safely, and in order for us to move forward and deliver events of this scale we must plan ahead, be flexible and prepared for change.
"Getting the Autumn Nations Series on sale early is an essential step in this process."
And Wales head coach Wayne Pivac said: "There is no doubt this is a huge autumn series fixture list, and we are already looking forward to it, especially with the prospect of having supporters back at the Principality Stadium.
"It would be close to 21 months since we have had the chance to play in front of our fans at our home stadium, so it is hugely-exciting to have the fixtures announced, and I hope it excites the rugby public.
"As a group, we haven't faced a southern hemisphere side yet, with last year's summer tour cancelled and autumn series rejigged, so we are looking forward to welcoming all four sides to Cardiff for what will be four huge Test matches."
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