The wild run through the streets of Pamplona kicked off at 8am, lasting just 25 seconds as people, with many wearing traditional white clothing and red neckerchiefs, scrambled to avoid getting caught on bull horns.
One 52-year-old man was injured after a bull gored him in the thigh, while three others received fractures, Spain's La Vanguardia newspaper reported.
Last year 50 people were taken to hospital at the festival's eight runs, including 23 revellers caught in a bloody human pile-up on the final day of the fiesta.
Several hundred more were treated for minor injuries at the scene. Most injuries are not caused by bull horns but by runners falling, or being knocked over or trampled by the animals.
Fifteen people have been killed in the bull runs since records started in 1911.
The most recent death took place four years ago when a bull gored a 27-year-old Spaniard in the neck, heart and lungs.
In a bid to stop such incidents, Pamplona's city hall has this year introduced fines of up to €60,000 euros ($82,000) for those that violate rules intended to minimize the risk of the bull runs.
Using a camera during a bull run or taking part while drunk are among the acts prohibited under a new city ordinance.
"We have a problem since there are people who enter the bull run who don't really know what a bull run is," Pamplona city councillor Fermin Alonso, who is responsible for cultural activities, told news agency AFP.
"Pamplona police have to remove from the course drunk people, people who wear sandals instead of running shoes. To correct these situations we have established some norms and fines."
Monday's event saw the first such fine being imposed after a British veteran of the event was penalized for crossing the orange waiting line at the beginning of the bull run, according to Basque television broadcaster Eitb.
The city of 300,000 residents expects the festival, made famous worldwide by Ernest Hemingway's 1926 novel "The Sun Also Rises", will draw between 750,000 and over one million visitors.
Ana Caroaizcorbe, 43, has returned to the festival for the first time since she was a child.
"It seems much more massive now… but the bull runs, the religious acts, I think they still have a traditional character," she said.
Over 150 animal rights campaigners daubed themselves in fake blood and stood in Pamplona's main square on Saturday holding signs that read in several languages: "You Run. Bulls Die."