"The placement of elements of a U.S. global missile shield in Eastern Europe will only aggravate the situation," Medvedev said at a meeting with senior Russian diplomats in Moscow.
Moscow has strongly opposed the possible deployment by the U.S. of 10 interceptor missiles in Poland and an accompanying radar in the Czech Republic as a threat to its security and international nuclear deterrence. Washington says the defenses are needed to deter a possible strike from Iran.
During their visit to Moscow in late March, U.S. Defense Secretary Robert Gates and Secretary of State Condoleezza Rice offered to let Russia monitor the proposed U.S. missile and radar bases in Central Europe in order to allay Russian concerns.
Washington has also offered not to activate the system until there is a "clear and present" threat from Iran or other potential adversaries.
But Russia said the U.S. proposals were vague and nontransparent.
"Security cannot be based on word of honor alone," Medvedev reiterated on Tuesday.
On an official visit to Germany in early June, he called for a legally binding European security treaty to be signed at a pan-European conference.
Medvedev said any new security arrangements should be based on "pure" national interests, not skewed by ideological motives. He added that "organizations operating in the Euro-Atlantic region" should also have the opportunity to join.