The Illuminados created four Gigantes which were positioned in different locations. US SOCOM agent Leon Kennedy was forced to fight each one of them. The first was brought out from the cult's Plaga mines to kill Leon when he first attempted to free Ashley Graham from her captivity. The beast killed its Ganado handlers and attacked Leon, but Leon recieved unlikely aid in the form of a dog that he had freed from a trap in the woods outside of El Pueblo. The dog leapt down from the hills into the pit where the Gigante was held and distracted the monster so that Leon could open fire on it from behind. After being significantly wounded, the Plaga within the giant's body erupted from its back. Leon fired on the parasite and killed it, which in turn killed the Gigante.
Leon and Ashley would encounter a second Gigante as they attempted to flee the village. This one cornered the pair within a barricaded gorge, but Leon and Ashley were saved by mysterious spy Ada Wong, who killed the monster by damaging a platform holding a large boulder above the Gigante's head.
Leon would encounter two more Gigantes in the mines beneath Castle Salazar and had to battle them both at once inside a chamber filled with lava. The heavy metal grille floor above the lava had a hatch in its centre and Leon was able to kill one of the giants quickly by luring it onto the hatch and shooting out the switch that opened the hatch. With one of the giants dropped into the lava, Leon had only one to fight conventionally and was able to defeat it as he had the first giant he encountered.
El Gigante's skin is very resilient and can take a lot of punishment. It uses its sheer size and strength to crush enemies underfoot, though also picks up objects such as trees and boulders to use as weapons.
Gigantes can be stunned using conventional firepower, though in excessive amounts. It is unwise to attack it from the front and so its back makes the ideal target area. Since Gigantes are rather stupid, they can be easily distracted when there are multiple targets. After taking enough damage, the Gigante will become stunned and the Plaga parasite within its body will erupt from its back. Killing the parasite will kill the giant. Distance is recommended as anyone too close to the creature could be crushed when it keels over.