Authorities in San Antonio, Texas, found more than 40 bodies in a truck trailer, and pictures on social media showed police cars and ambulances surrounding the large truck.
San Antonio television station KSAT, citing police sources, said 42 people were found dead inside the trailer.
The channel reported that the truck was found next to railroad tracks in the city's Southwest Side neighborhood.
"Forty-six people died due to the intense heat inside the truck, which was carrying migrants," the head of the San Antonio fire department was quoted by the French news agency AFP as saying.
He described the incident as "a potential new immigration tragedy, especially since trucks are a primary means of smuggling clandestine immigrants to the United States."
San Antonio is located 240 km from the border with Mexico.
Pictures posted by a KSAT reporter on Twitter showed police cars and ambulances surrounding a large truck.
"The bodies that were found in San Antonio were in a truck carrying immigrants," Reuters quoted the Texas governor as saying.