Officials gave different death tolls in the immediate aftermath of the accident. Alberto Nunez Feijoo, president of the region of Galicia, said at least 35 people aboard the train were killed.
Spain's leading Cadena SER radio station cited the president of the Galicia's main court, Miguel Angel Cadenas, at the scene saying 56 people were killed, but that could not be independently confirmed. The station said three carriages had still to be inspected by rescue workers.
State-owned train operator Renfe said in a statement that 218 passengers and an unspecified number of staff were on board at the time of the accident. Renfe, which did not give a death or injury toll, said the derailment happened at 8.41 p.m. (1841 GMT) along a high-speed section that had been inaugurated just two years ago.
The SER radio station cited unnamed local government officials as saying 100 people were injured but there were no details on the severity of the injuries.
Feast day festivities planned in the city of Santiago de Compostela, outside of which the train derailed, were cancelled, town hall spokeswoman Maria Pardo told Spanish National television TVE.
Sergio Prego, a passenger on the train, told the SER, "The train was going at a very fast speed and in the curve it went off the tracks, it overturned. We were the lucky ones that were able to get out on our own feet.
"Victims? For sure. I have no idea but there must be an awful lot," he said.
A photographer at the scene said he saw dozens of what appeared to be dead bodies being extracted from the wreck by emergency workers. TVE showed footage of what appeared to be several bodies covered by blankets alongside the tracks next to the damaged train wagons and rescue workers entering toppled carriages through broken windows.
The photographer, Xabier Martinez, told The Associated Press that he also spoke to two injured train passengers who said they felt a strong vibration before the derailing.
The accident occurred near the train station in Santiago de Compostela, 95 kilometers (60 miles) south of El Ferrol, the final destination. Rescue workers were also seen in the television images caring for people still inside some of the wagons.
Television footage showed one wagon pointing upwards into the air with one of its ends twisted and disfigured. Another carriage that had been severed in two could be seen lying on a road near the track.
The train, which belongs to the state-owned Renfe company, had started its journey in Madrid. Although it was not an AVE high speed train, it was a relatively luxurious version that uses the same track as Spain's fastest expresses.
It was Spain's deadliest train accident in decades. In 1944, a train traveling from Madrid to Galicia crashed and killed 78 people. Another accident in 1972 left 77 dead on a track to southwestern Seville, according to Spanish news agency Europa Press.
Officials at the Interior Ministry and the Adif rail infrastructure authority did not immediately answer telephone calls or return messages seeking comment. Officials with Renfe also did not immediately return messages seeking comment.
King Juan Carlos and Prime Minister Mariano Rajoy, a native of Galicia, both offered their condolences. Rajoy announced he would visit the site Thursday.
Associated Press writer Alan Clendenning contributed to this story.