Wiping out the Haitian voodoo gang Les Serviteurs (who were using Predator cloaking devices) and the violent drug dealers called The Dead Men (who were dealing in Prometheus weapon tech), Scarface takes the skull of Serviteur houngan King Willie and the skulls of the Dead Men Triad. Thus, Scarface regains his honor by battling the various factions in order to recover the Predator technology (known to the humans as 'Prometheus' technology). The warring factions all pay tribute to Lucretia Borgia, daughter of Hunter and granddaughter of Bruno. The Predator technology, derived from Scarface's abandoned equipment, has proliferated into the hands of Bruno's descendants and warring gangs who have utilized it in New Way City, now known as Neonopolis - City of Light, as well as against other Predators.

One hundred years later, the Predator, now called Scarface, is offered a chance for redemption. Shamed by defeat and having exposed his race to the humans, the Predator is exiled by his clan to a planet inhabited by deadly alien creatures. The Predator then sets off his ship's self-destruct sequence however, this fails to kill him as he is outside the range of the explosion. As he attempts to reach his ship, the roof he is running across collapses - leaving him incapacitated. The Predator makes a hasty escape, leaving behind some of his equipment. Bruno's wife Isabella shoots the Predator in the eye, causing his blood to splatter on her and her newborn son Hunter.

The player controls a Predator who stalks and kills mob boss Bruno Borgia and members of his gang who are at war with the Irish Mob. During gameplay, the Predator generally emits lion, tiger, leopard, and jaguar growls. In first-person mode, the player can use vocal mimicry to distract or lure an enemy, while in third-person mode the player can emit a roar. The player can also use items, such as medical kits which restore health. Weapon upgrades are found in some of the stages. A number of the weapons reflect those used in the Predator and Alien vs. A variety of weapons are used in the game, falling into the categories of melee and ranged weapons. The game also has several bonus missions in which the player can earn rewards including costumes, weapons, and increased health and energy.

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