In Warhammer 40,000: Space Marine II, the player engages enemies using a mix of both melee and ranged combat from a third-person point of view.[2] The player controls Titus, a lieutenant of the Ultramarines chapter and returning protagonist from the first game. Titus is accompanied by fellow Space Marines Chairon and Gadriel throughout the campaign who can be controlled by other players in the game's cooperative multiplayer mode or by artificial intelligence (AI) in single player.[3][4]

The game utilizes ranged combat when facing weaker enemies (such as Tyranid Gaunts), while hack and slash combat is required when fighting more powerful enemies (such as the Tyranid warrior) that can block incoming projectile damage. Players can parry an opponent's attack, though some hostile attacks are unblockable and therefore must be dodged. Additionally, the player can fight alongside imperial guard foot soldiers controlled by AI throughout sections of the game. Titus is protected by armor. When his armor breaks, his health will drop permanently when he is attacked. Health will only replenish when the player recovers medkits in the game's battlefield. His armor, however, will regenerate after Titus performs an execution attack on an enemy.[5] If a character's health is depleted the character will drop to the ground and bleed out for 30 seconds during which other characters can revive them before they die.[6]

The game also supports a separate cooperative mode named "Operations”, and three 6v6 competitive multiplayer modes (Annihilation, Seize Ground, and Capture and Control). Players can choose from six different character classes and freely customize their player avatar with various cosmetic items

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