Delegates voted on Friday to allow people in life-long monogamous gay relationships to become ministers. The Evangelical Lutheran Church in America (Ecla) is one of the largest to open the role to gay men and women.
The decision comes a month after the Anglican Church in the US voted to allow the ordination of gay bishops.
Two-thirds of delegates voted in favour of the change at the Lutheran Church's national assembly in Minneapolis on Friday. It followed impassioned argument about whether or not the Bible forbids active homosexuality, and left a number of delegates in tears.
Some traditionalist clergy told the assembly they would leave the Church, and predicted an outflow of Lutherans to join other churches or create their own denomination.
The decision by the 4.5-million strong Lutheran Church is significant because of its position roughly in the middle of Protestant theology, and it will add to a sense of momentum towards a more liberal approach to homosexuality among American churches.
Other Protestant denominations - including the Presbyterian Church - have recently opted not to take a similar step, but by a narrower margin than before.
Anglicans who have left the Episcopal Church because it ordained a gay bishop have formed a rival traditionalist Church.
Cry moar. Literally. Two-thirds voted in favour, SUCK IT UP.