An American who co-wrote a book called How to Survive the Running of the Bulls was badly gored on Wednesday in the morning bull run at Pamplona's San Fermin festival.
A Spanish man was also gored in the "encierro", when runners in red scarves and white outfits dash through the Spanish town's streets pursued by the huge animals.
Chicago resident Bill Hillmann, 32, tripped and fell when a bull gored him in his right thigh, according to festival website sanfermin.com.
The Spaniard, a 35-year-old man from Valencia, was gored in the chest and taken to hospital in a semi-conscious state, officials said. The two men are in a serious condition, the regional government said.
A further three men, all Spanish, were taken to hospital with lesser injuries from the chaotic stampede through the narrow streets of Pamplona's old town, authorities said. All the injured were men. Few women take part in the run. Authorities did not give the names of the injured men.
Wednesday's run was the third in the week-long San Fermin festival, depicted in Ernest Hemingway's 1926 novel The Sun Also Rises.
The daily bull run starts at 8am and usually lasts around three to five minutes. It ends at the bull-ring, where the bulls are corralled before reappearing in the evening bullfight, when they are killed.
San Fermin has become a global tourist attraction, with tens of thousands of Spaniards and foreigners pouring into the Navarran capital. Many participants drink and dance all night.
Hemingway aficionado Hillmann travels to Pamplona every year to take part in the festival.
The black bull that gored him was the heaviest of the morning's six bulls from the Victoriano del Rio ranch, weighing around 600 kilos.
A 27-year-old man from Madrid was the last person to be killed during the bull run after being gored in the neck in 2009. There have been 14 fatalities over the past century at the fiesta, which dates to the 13th century.