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While the match will take place at Windsor Park, Northern Ireland's national stadium, it will be played under UEFA's Return To Play protocol, meaning fans won't be in attendance.
It is one of two matches the U.S. expects to play in Europe in March.
The USMNT is looking at a busy 2021, with participation in the CONCACAF Nations League, the CONCACAF Gold Cup, and World Cup qualifying all on the schedule.
It is expected that manager Gregg Berhalter will bring in mostly European-based players for the match.
"This is a good opportunity to work with our full group before the Nations League Final Four in June," Berhalter said. "We've been excited about the progress our players continue to make with their clubs, and now we have another chance to strengthen our group ahead of the start of World Cup qualifying later this year. Northern Ireland is a very competitive team and brings a different set of challenges in the way they play. We look forward to a great experience."
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The encounter will be the first in 70 years between the two sides. On Aug. 11, 1948 Northern Ireland prevailed 5-0.