In Yokohama, vampire hunter Blade attacks a vampire feeding ground, which is camouflaged as a nightclub and acts as a front for the Asian vampire group, Existence. Teaming up with a Japanese father-daughter team of vampire hunters, Hayate and Makoto, Blade vanquishes all of the vampires. However, amidst the carnage, Blade realizes that Deacon Frost, the vampire who killed Blade's mother, is the head of Existence and is forced to make a decision that will change Makoto's life forever.
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Sakomizu, a middle-aged police detective in Osaka, is troubled by a recent series of missing Southeast Asian women. After he meets up with Blade, they discover that the chief of police is helping to provide local vampires with human blood. To put an end to this, Blade and Sakomizu enter an abandoned metro line where Existence has created human 'crop fields' and there, Blade is attacked by a Japanese entity known as a Suiko (water tiger) just as Makoto, the female vampire hunter, arrives seeking revenge.
Aboard a cargo ship heading for the Philippines, Blade departs Kobe Harbor hot on Deacon Frost's trail. On the ship, Blade's mentor, Noah Van Helsing, injects him with a retro-virus to suppress his urge to drink blood and while out of commission, Van Helsing reveals to Makoto the secret origin of Blade. Still reeling from the after-effects of his injection, Blade finds himself unable to fight when a swarm of Mandurago vampires attack the ship.
Determined to rescue his mentor, Van Hesling, from the clutches of a pack of Mandurago vampires, Blade tracks him to a local slum in the Philippines. Reminded of his own childhood, he shares with Makoto how he was forced to kill his own mother who had been turned into a vampire. Together he and Makoto hatch a plan to rescue Van Helsing from the local Existence branch.
Siquijor Island, the location of an Existence research facility, is home to the Berdugo tribe who have used white magic to keep vampires under control since ancient times. Against the wishes of the Berdugo, Blade and Makoto set out in search for Frost's facility. However, before they can get far, they are attacked by Manananggal, a breed of vampire unlike any Blade has seen before.
In his quest for Frost, Blade travels to the Island of Sumatra in Indonesia and launches an attack on a silver mine operated by Existence. There Blade and Makoto come into conflict with a witchdoctor who claims to have a cure for vampirism.
Blade arrives in Madripoor and is instantly attacked by a local gang when an old acquaintance, Wolverine, appears. Lucius Isaac who controls this local gang is also a servant from the pureblood vampire High Council whose aim is to destroy Existence. When Isaac attacks, it leads to all out melee between the three.
In the jungles of Vietnam, Blade is attacked by a band of vampire ninjas. Rescued by an American Soldier, Blade learns of a secret U.S. Military initiative called the "V Plan". But before Blade can unravel its secrets, he is confronted by a mysterious attacker.
Blade has no choice but to fight the mutant assassin, Kikyo Mikage. Former classmates under a prestigious master swordsman in Japan, they now find themselves on opposite sides. But before they can finish their battle, everything is turned upside down when their former mentor makes a surprise appearance.
A captured Blade is taken to the Existence research lab known as 'The Factory' to be experimented on by Deacon Frost who divulges his own awful ambitions. Meanwhile, Makoto puts everything on the line to rescue the Daywalker.
While in captivity and pushed to his limits, Blade struggles to regain control of himself as his allies attempt a daring rescue. But a price will be paid for their efforts against Frost and his vampire forces because not everyone will make it out alive…
Blade invades Amaurot, the City of Vampires and headquarters of Existence, while cutting his way through anything that stands between him and Deacon Frost. Meanwhile, Van Helsing and Kikyo Mikage engage in fierce battles of their own. In the final confrontation between Blade and Deacon Frost, who will triumph?