The Missouri Compromise, also called the Compromise of 1820, was an agreement passed in 1820 between the pro-slavery and anti-slavery factions in the United States, involving primarily the regulation of slavery in the western territories.

A bill to enable the people of Missouri Territory to draft a constitution and form a government preliminary to admission into the Union came before the House of Representatives in Committee of the Whole, on the February 13, 1819. An amendment offered by James Tallmadge of New York, which provided that the further introduction of slaves into Missouri should be forbidden, and that all children of slave parents born in the state after its admission should be free at the age of 25, was adopted by the committee and incorporated in the bill as finally passed on February 17, 1819 by the house.

The United States Senate refused to concur in the amendment, and the whole measure was lost. During the following session (1819-1820), the house passed a similar bill with an amendment introduced on the January 26, 1820 by John W. Taylor of New York making the admission of the State of Missouri conditional upon its adoption of a constitution prohibiting slavery. In the meantime the question had been complicated by the admission in December of Alabama, a slave state (the number of slave and free states now becoming equal), and by the passage through the house (January 3, 1820) of a bill to admit Maine as a free state.

The Senate decided to connect the two measures, and passed a bill for the admission of Maine with an amendment enabling the people of Missouri to form a state constitution. Before the bill was returned to the house, a second amendment was adopted on the motion of Jesse Burgess Thomas of Illinois, excluding slavery from the Missouri Territory north of 36° 30’ (the southern boundary of Missouri), except within the limits of the proposed state of Missouri. The House of Representatives refused to accept this and a conference committee was appointed.

There was now a controversy between the two houses not only on the slavery issue, but also on the parliamentary question of the inclusion of Maine and Missouri within the same bill. The committee recommended the enactment of two laws, one for the admission of Maine, the other an enabling act for Missouri without any restrictions on slavery but including the Thomas amendment. This was agreed to by both houses, and the measures were passed, and were signed by President James Monroe respectively on March 3 and on March 6 of 1820. When the question of the final admission of Missouri came up during the session of 1820-1821, the struggle was revived over a clause in the new constitution (1820) requiring the exclusion of "free negroes and mulattoes" from the state. Through the influence of Henry Clay an act of admission was finally passed, to come into operation as soon as the state legislature would pledge itself not to pass any legislation to enforce this clause. This is sometimes known as the second Missouri Compromise.

These disputes, involving as they did the question of the relative powers of Congress and the states, tended to turn the Democratic-Republicans, who were becoming nationalized, back again toward their old state sovereignty principles to prepare the way for the Jacksonian-Democratic Party. On the other hand, the old Federalist nationalistic element was soon to emerge first as National Republicans, then as Whigs, and finally as Republicans.

On the constitutional side, the Compromise of 1820 was important as the first precedent for the congressional exclusion of slavery from public territory acquired since the adoption of the Constitution, and also as a clear recognition that Congress has no right to impose upon a state asking for admission into the Union conditions which do not apply to those states already in the Union. The compromise was specifically repealed by the Kansas-Nebraska Bill of 1854.