The blast occurred as U.S. vehicles were passing near an Iraqi police checkpoint in Mosul, Iraq's third largest city and the last major urban battleground in the war against al Qaeda and other Sunni insurgents.
A U.S. statement said three U.S. soldiers were killed at the scene. A fourth soldier and an Iraqi interpreter died of wounds at a military hospital, the U.S. said.
An Iraqi police official, who spoke on condition of anonymity because he wasn't authorized to release the information, said two Iraqi policemen and one civilian were wounded in the blast.
It was the deadliest single attack against U.S. troops since May 2, 2008, when four Marines were killed in a roadside bombing in Anbar province, a former insurgent stronghold west of Baghdad.
Four U.S. soldiers were killed Jan. 26 when two helicopters collided in midair near the northern city of Kirkuk, but U.S. officials said the crash did not appear due to hostile fire.
The latest deaths raised to at least 4,243 the number of U.S. military members who have died since the Iraq war began in March 2003, according to an Associated Press count.
American casualties have fallen to some of their lowest levels of the war since thousands of Sunnis abandoned the insurgency and U.S. and Iraqi forces routed Shiite militias in Baghdad and Basra last spring.
Only five of the 16 U.S. service members who died in Iraq last month were killed in action.
However, fighting continues in Mosul and elsewhere in northern Iraq a conflict which U.S. officials say is driven in part by ethnic rivalries between Sunni Arabs and Kurds.
Many Sunni extremists are believed to have fled to the north after being driven from longtime strongholds in Baghdad and central Iraq.
Despite a sharp drop in bombings, shootings and killings, security controls remain intense throughout much of the country because of concern that violence could flare again because of the slow pace of political agreements among the country's ethnic groups.
The government announced Monday that tens of thousands of Iraqi security forces had been stationed along routes leading to the Shiite holy city of Karbala to protect religious pilgrims marching there for rituals this week.
Attacks by al Qaeda in Iraq, other Sunni insurgents, Shiite extremists and a Shiite cult have killed hundreds of people during pilgrimages in recent years.
Hundreds of thousands of Shiite pilgrims are expected to visit Karbala by next Monday to mark the end of 40 days of mourning that follow Ashoura, the anniversary of the seventh century death of the Prophet Muhammad's grandson Hussein.
He was killed in a battle for the leadership of the nascent Muslim nation following Muhammad's death in 632.
Also Monday, two Iraqi security officials said four Iraqis transferred here from the U.S. detention center at Guantanamo Bay were being interrogated.
The officials said the men had been arrested in Afghanistan and held at Guantanamo before being handed over to the Iraqis last month. The officials spoke on condition of anonymity because they were not authorized to speak to the media.
President Barack Obama has ordered the detention center in Cuba to be closed within a year as part of his overhaul of U.S. national security policy. An estimated 245 men are being held, most of whom have been detained for years without being charged.
A Shiite woman in Basra told The Associated Press that one of the four was believed to be her brother, Hassan Abdul-Hadi Abdul-Said al-Jawhar, who disappeared in 1999 while serving with the Iraqi army in northern Iraq.
The family heard nothing from him until 2004, when it received a handwritten letter from him indicating he was in Guantanamo.
Neda Abdul-Hadi said her family was told Sunday by the International Committee of the Red Cross that her brother was back in Iraq but she had been unable to communicate with him. She said the family had received no word from Iraqi authorities about his whereabouts.
The Red Cross said it would not comment on individual cases. The Pentagon announced Jan. 17 that it had transferred six detainees from Guantanamo four to Iraq and the others to Algeria and Afghanistan but did not give their names.
Hugh Handeyside, a Seattle lawyer whose firm had filed a motion for release on al-Jawhar's behalf, told the AP by telephone that he had been detained in Afghanistan in 2002 under "circumstances which are classically murky."
He was never charged, Handeyside said.