The US–UK Mutual Defense Agreement, or 1958 UK–US Mutual Defence Agreement, is a bilateral treaty between the United States and the United Kingdom on nuclear weapons co-operation. The treaty's full name is Agreement between the Government of the United States of America and the Government of the United Kingdom of Great Britain and Northern Ireland for Cooperation on the uses of Atomic Energy for Mutual Defense Purposes. It allows the US and the UK to exchange nuclear materials, technology and information. The US has nuclear co-operation agreements with other countries, including France and other NATO countries, but this agreement is by far the most comprehensive. Because of the agreement's strategic value to Britain, Harold Macmillan (the Prime Minister who presided over the United Kingdom's entry into the agreement) called it "the Great Prize".

The treaty was signed on 3 July 1958 after the Soviet Union had shocked the American public with the launch of Sputnik on 4 October 1957, and the British hydrogen bomb programme had successfully tested a thermonuclear device in the Operation Grapple test on 8 November. The special relationship proved mutually beneficial, both militarily and economically. Britain soon became dependent on the United States for its nuclear weapons since it agreed to limit their nuclear program with the agreement of shared technology. The treaty allowed American nuclear weapons to be supplied to Britain through Project E for use by the Royal Air Force and British Army of the Rhine all the way up until the early 90s when the UK became fully independent in designing and manufacturing its own warheads.

The treaty provided for the sale to the UK of one complete nuclear submarine propulsion plant, as well as ten years' supply of enriched uranium to fuel it. Other nuclear material was also acquired from the US under the treaty. Some 5.4 tonnes of UK-produced plutonium was sent to the US in return for 6.7 kilograms (15 lb) of tritium and 7.5 tonnes of highly enriched uranium (HEU) between 1960 and 1979, but much of the HEU was used not for weapons but as fuel for the growing fleet of British nuclear submarines. The treaty paved the way for the Polaris Sales Agreement, and the Royal Navy ultimately acquired entire weapons systems, with the UK Polaris programme and Trident nuclear programme using American missiles with British nuclear warheads.

The treaty has been amended and renewed nine times. The most recent renewal extended it to 31 December 2024.