Several others people were hospitalized for treatment of head injuries and other less serious injuries, said Jose Aldaba, spokesman for the Red Cross.
The pack of six 1,300-pound bulls and six steers - meant to keep the bulls running in a single pack - disintegrated shortly after the animals set off on the dash through the cobblestone streets of Pamplona in the sixth of eight planned runs.
One stray bull turned around and ran the wrong way. Herders with long sticks smacked it in the rump to get the animal pointed in the right direction.
The loose bull charged and tossed several runners - some of them clad in the traditional red-and-white garb of San Fermin - on its way to the bullring.
Several runners were trampled and at least four were injured by bulls' horns, Aldaba said. One man was reportedly gored in the chest. Nationalities and names of the injured were not immediately released.
The run lasted 6 minutes, 9 seconds, compared with the normal length of about 2 minutes, because the bulls separated - the most dangerous thing that can happen at Pamplona.
The festival in this northern town, renowned for its all-night street parties, dates back to the late 16th century. It gained worldwide fame in Ernest Hemingway's 1926 novel "The Sun Also Rises."
Since record-keeping began in 1924, 13 people have been killed during the runs, the most recent in 1995.