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Established in 1932 as a new primary routing, it initially ran from US 70/NC 10 (now NC 55), in Fort Barnwell, to NC 43, in Vanceboro.
By 1950, NC 581 extended again on new primary routing south to US 70, then east replacing NC 111, ending at US 70 Bus/US 117 Bus, in downtown Goldsboro.