"The Bulgarian nurses have been too long in captivity," Rice said following a ceremony to open Bulgarian military bases to wider U.S. use. "This is a humanitarian case and it is time for them to come home."
The issue has complicated the warming of U.S. relations with Libya.
The nurses and a Palestinian doctor have been held in Libya since 1999. They were convicted in May 2004 on charges of intentionally infecting children at the al-Fath Children's Hospital in Benghazi as part of an experiment to find a cure for AIDS.
In Sofia where Rice was meeting with NATO leaders, the secretary inked an agreement with the Bulgarian government granting U.S. troops access to military facilities in the country.
The deal is part of a strategy of shifting troops based in Europe farther east and will deploy up to 2,500 U.S. troops to Bulgaria. It has raised suspicions in Bulgaria that the United States could one day use European soil to launch a military strike on Iran if it refuses to rein in its disputed nuclear program.
Tehran faces a Friday deadline from the Security Council to stop enriching uranium, a process that can lead either to nuclear power for electricity or to development of weapons. Iran says it only wants to generate electric power
"It's pretty clear Iran is not going to meet those requirements," Rice said. "When that happens the international community, represented by the Security Council, is going to have a choice."
"Is the Security Council going to be credible?" Rice said after meetings with NATO foreign ministers.
Quick action by the council to impose economic or punitive sanctions seems remote because of splits among its members. The United States is pressing for a strong response, and Rice wants such steps to remain an option.
The United States and European allies accuse Iran of hiding ambitions to build a bomb behind a legitimate energy program. Iran denies it but says it must retain control of sensitive nuclear technology, including uranium enrichment.
The United States has long sought the Security Council review now under way, but the powerful U.N. body is divided over what to do next.
The basing agreement with Bulgaria concludes five days of diplomatic meetings in Europe and Iraq, where Rice and Defense Secretary Donald H. Rumsfeld made an unannounced visit to support the country's newly selected leadership.
The United States will have wider use of four military facilities in Bulgaria, giving American forces a jumping-off point closer to potential hotspots in the Middle East.
"We look forward to continued work with Bulgaria and with all of our colleagues to meet the tremendous challenges that we all face around the world, from terrorism, from proliferation of weapons of mass destruction," Rice said. "These are common threats."
American officials want to deploy troops on rotational training tours as part of a broader U.S. strategy of shifting troops based in Europe further east. The U.S. is interested in small, flexible bases, different from those set up to house large numbers of troops during the Cold War.
Bulgaria, a Balkan country of 7.8 million people, joined NATO in 2004 and hopes to join the European Union next year. Bulgarian officials have said the agreement would help improve Bulgaria's armed forces, boost its economy and enhance security.