The run lasted just under four minutes and produced panic when some bulls separated from the pack. One stopped just before entering the bullring and paced in circles threateningly while staring at the runners.
Television images showed the first runner being gored in the chest and hurled to the cobblestones of a narrow street in Pamplona's historic old quarter. He remained on the ground dazed until he was taken away by rescue workers.
One man sustained serious injuries after being gored in the thorax, while a second man was gored in the left leg but was in better condition, said Fernando Boneta, a doctor at Navarra Hospital.
The more seriously injured man was a 22-year-old Spaniard, while the other goring victim was a 43-year old man from Britain, authorities said. The men were identified only by their initials.
Five more people were hospitalized in Pamplona for less serious injuries, mostly broken bones and bruises from falls as they ran, though TV images clearly showed other people being trampled. Those still hospitalized Thursday afternoon included a 48-year-old American, a 33-year-old Israeli and one Spaniard, the Navarra regional government said. Two other Spaniards were treated and released.
Thursday's gorings were the first for eight bull runs held during the nine-day street festival, which also features around-the-clock drinking that attracts tens of thousands of people eager to party.
Cody Harrington, 22, was amazed at the size of the 1,100-pound (500-kilogram) bulls as he ran alongside them for the first time.
"They were about up to my shoulders, and it was intense," the university student from Lake Tahoe, California said. "Once I saw them running right next to me I got to the side and it was shocking how big they were."
His 62-year-old father ran as well.
"It was a rush, definitely an adrenaline rush, the street is so narrow, you're right next to them and then they're gone like a shooting star," said Jack Harrington, a dentist on a tour of Europe with his wife, son and two daughters.
An 18-year-old Australian who sustained three fractured vertebrae in the first race Wednesday remained hospitalized Thursday in serious condition, according to the El Diario de Navarra newspaper.
He was identified by the newspaper as Nicholas Ward of Melbourne, and the young man's father, Howard, told the newspaper his son was expected to remain hospitalized for two weeks.
An American was also injured Wednesday in another event during the San Fermin party in which horned juvenile cows weighing about 400 pounds (180 kilograms) are released into a bullring to be taunted by young men.
The unidentified 22-year-old man sustained a torn scrotum from a horn injury, El Diario de Navarra said. The newspaper did not list his hometown.
While gorings from the adult bulls with their huge horns and incredible weight are more likely to be fatal or cause serious injuries, the juvenile cows are also dangerous because they are more frisky.
The runs are broadcast live on Spanish television and the bulls that run each morning are killed in the evening in the bullring, their meat served up in Pamplona's restaurants.
Dozens of people are injured in the runs each year. Gorings produce the most dramatic injuries and generate extensive comment in Spain's media. Last year's festival saw the first fatal goring in nearly 15 years.
In the northeastern Spanish region of Catalonia, meanwhile, a legal advisory body said the area's regional parliament can go ahead with a vote this month on banning bullfighting. It ruled any prohibition voted on by the parliament would not violate Spain or Catalonia's charters.
The proposed ban is part of an animal rights bill.
The Catalan parliament said it will vote on July 28. If approved, Catalonia would become the second Spanish region to ban bullfighting after the Canary Islands did so in 1991.
The ban would shut down Catalonia's last bullring in Barcelona, though it won't ban other bull spectacles like "correbou," where people chase bulls through the streets or "bouembolat," where bulls run around with flaming wax balls on their horns.