Scottish referee Hollie Davidson will become the first female to officiate a Test involving a men's Six Nations team when Portugal host Italy on 25 June.
Davidson took charge of her first men's Test in 2019 when Malta beat Cyprus in the Rugby Europe Conference 1 South.
And last week she was named as an official for the delayed 2021 Rugby World Cup.
Davidson said it was "a tremendous honour and an achievement I am proud of" to take charge of Italy's game.
"I have been happy with my progress in the last couple of years and working as a full-time professional referee with Scottish Rugby has really helped that," she told the governing body's website.
"I couldn't believe it when I heard the news as I didn't think something like this would have happened so quickly in my career but I'm really proud and looking forward to the summer."
For Portugal v Italy, Davidson will lead an all-female team with Sara Cox (England) and Aurelie Groizeleau (France) being her assistant referees, and Claire Hodnett (England) as the Television Match Official (TMO).
In addition, the Scot will take charge of Canada v Belgium on 2 July, another men's Test.
Already this season she has refereed three matches in the United Rugby Championship - Glasgow Warriors v Edinburgh, Ulster v Cardiff Blues, Ospreys v Munster - along with France v England in the 2022 Women's Six Nations.