Two of the Americans kidnapped at gunpoint in Matamoros, Mexico, have been found dead, Mexican authorities reported on Tuesday.
The two other missing Americans were found alive. They have since been returned to the US, where they are receiving medical treatment, the State Department confirmed.
"We're providing all appropriate assistance to them and their families," said State Department spokesman Ned Price.
Mr Price added that the US was "in the process of working to repatriate remains of two Americans killed".
The four US citizens had travelled to Mexico on Friday so that one of them could receive medical care, their families confirmed to media.
The Americans have been identified as Latavia Washington McGee, Shaheed Woodard, Zindell Brown and Eric James Williams.
They had entered Matamoros via Brownsville, Texas.
Matamoros, a border city of more than 500,000, is located in the state of Tamaulipas, one of six districts that the US State Department has advised US citizens to avoid.
“Criminal groups target public and private passenger buses, as well as private automobiles travelling through Tamaulipas, often taking passengers and demanding ransom payments,” the State Department's travel advisory says.
The city has been wracked by drug cartel violence in recent years, with frequent clashes between the Gulf Cartel — which has historically controlled it — and the Zetas. Mexican authorities have also clashed with the cartels in the city.
The FBI had been searching for the missing Americans after they were kidnapped, issuing a $50,000 reward for information leading to their rescue.
"Our immediate concerns are for the safe return of our citizens, the health and the well-being of those who survived this attack," said John Kirby, spokesman for the National Security Council.
Mr Kirby said that Washington was going to "work closely with the Mexican government to ensure that justice is done in this case".
A video posted online appears to show the moment the Americans were taken at gunpoint, with armed men in bulletproof vests dragging the hostages across the street before dumping them in the back of a pickup truck.
"Our thoughts are with the families of these individuals and we stand ready to provide all appropriate consular assistance, and US law enforcement is in touch with Mexican law enforcement," White House spokeswoman Karine Jean-Pierre said on Monday.
CNN reported that officials believe the four may have been taken by mistake.
The US ambassador to Mexico, Ken Salazar, said that an "innocent Mexican citizen was tragically killed" in the incident.
"US law enforcement officials from numerous agencies are working with Mexican authorities at all levels of government to secure the safe return of our compatriots," Mr Salazar said.
Agencies contributed to this report