In a lavish chamber within the Czech capital's presidential castle complex, the two presidents put their names to history. The treaty must be now be ratified by Russia's parliament and by the U.S. Senate, where the White House lobbying effort is under way.
"Today is an important milestone for nuclear security and nonproliferation, and for U.S.-Russia relations," Obama said. Medvedev hailed the signing as a historic event that would launch a new chapter of cooperation between the countries.
The new treaty will shrink the limit of nuclear warheads to 1,550 per country over seven years. That still allows for mutual destruction several times over. But it is intended to send a strong signal that Russia and the U.S. -- which between them own more than 90 percent of the world's nuclear weapons -- are serious about disarmament.
Inside the hall, the anticipated moment came as the two presidents picked up their pens, glanced at each other and grinned as they signed several documents, with aides transferring the papers back and forth so all would have both signatures. When it was done, the leaders seemed momentarily at a loss, with Medvedev flashing a smile and a shrug before they stood to shake hands.
Obama said the treaty sets a foundation for further cuts in nuclear arms.
And he pledged more conversation with Medvedev about missile defense, which remains a sticky issue between the countries as the U.S. moves ahead with plans it calls no threat to Russia.