Rise of the Vampires is a two month cross over between the series Peter Milligan's Justice League Dark and Joshua Hale Fialkov's I, Vampire, starting in March 2012. Prior to the actual cross over, in I, Vampire, Andrew Bennett's lover Mary, Queen of Blood began an uprising with her vampire army coordinating secret attacks across the US. The vampire uprising first came to the attention of the DCU heros when Mary and her horde travel to Gotham, eventually gaining the attention of Batman who briefly works with Andrew to fight the horde. The outcome of the battle sends shock waves through the mystic forces of the DCU, being felt by Madame Xanadu, who knows that her make shift team of the Justice League Dark must fight the new threat. The cross over would set the stage for many of the events that would follow in both the titles.
While in Gotham, fighting off Mary's hored with Batman, and his friend John Troughton, Andrew Bennett is seemingly slain by Tig, a young girl he had taken on, whose father turned into a vampire, killing her mother. Tig believes that if she kills Andrew, that Mary would fall, as well as her hoard. After being decapitated, Andrew's body fades away in a cloud of dust, but instead of all the other vampires following suit, the earth splits, and Cain, the sire of all vampires rises. Cain's awakening is so powerful, it is felt by Madame Xanadu, just as she was meeting with Zatanna, Deadman, Shade and Constantine. She warns her fellow magic users that "it has begun."
In Gotham, Cain takes control over Mary's horde, as he begins to siphon all magic from the world. The Justice League Dark transports themselves to Gotham with the help of Shade's M-vest, and the effects of Cain's magic siphoning are immediately felt, as the M-vest begins to malfunction. The team comes across Batgirl, aka Barbara Gordon fighting a gang of vampires. She informs the team briefly of what the situation is before she's called to another part of the city by Batman. Xanadu believes that the key to defeating Cain is retrieving Andrew from the realm of the dead, tasking Constantine and Deadman to do so, while she enters an astral plain, seeking for more help, while leaving her physical body in danger.
While Constantine and Deadman try to retrieve Andrew from the realm of the dead, Shade attempts to transport Zatanna and Xanadu's body to a safer location, but ends up on a rooftop where Batman, Tig, and John are fending off more vampires. With his allies in danger, Batman is forced to leave, leaving Zatanna in charge. As more and more vampires close in, while Zatanna and Shade's magic continues to weaken, Mary appears on the rooftop, entering a fragile alliance with the heros, as Cain angered her by taking the army she spent years trying to create.
Cain eventually releases a burst of magic energy, strengthening his vampire army, while heroes like Barbara Gordon, Dick Grayson, Catwoman, Batman and Damian Wayne do their best to fend off the beasts. While all this is happening, Andrew remains on a plain between life and death, neither heaven or hell, forced to watch the chaos, as a mysterious voice speaks to him, blaming him for the events at hand.
While chaos reigns in Gotham, Constantine and Deadman find Andrew within purgatory, asking him to come back in order to defeat Cain. Andrew denies the request, claiming that he is emotionally defeated, having no fight left in him. Meanwhile, in the astral zone of the Crystal One, Xanadu requests that the magical being help shift the tides of magic, in order to help defeat Cain, to which the Crystal One agrees. Xanadu wakes up back in Gotham, weakened, and to the sight of Shade having a complete metal breakdown, leading to his M-Vest to take him to a place outside reality where he meets his dead love Kathy George, never to be seen again. In an effort to go out fighting, Zatanna, Xanadu and Mary decide to attempt an attack on Cain, but find he's too powerful, leaving Zatanna to use the last of her magic to transport to Robinson Park, where Cain and his army follow. Deadman and Constantine show up empty handed. With the makeshift team seemingly defeated, and Cain's army closing in, the winds begin to blow, as the Crystal One's powers begin to take effect, as a resurrected Andrew Bennett appears before them, saying he found a little fight left in him.
Proclaiming that he has been made the exact opposite of Cain, Andrew uses his new powers to take control of the vampire horde, telling Mary that he's "seen the error of his ways" as the two lovers embrace and kiss. With the horde holding Cain, Andrew decapitates the primordial vampire, ending his threat. The Justice League Dark remains ever wary of Andrew, seeing that it seems that in order to defeat Cain, Xanadu traded one vampire threat for another. Mary calls for the horde to once again attack humanity, but Andrew stops her, saying they've exposed their secret too much, he then uses his new powers to make the world forget about that night, with the exception of the Justice League Dark and his associates. Before Andrew leads his kind to a new life, he's confronted by Constantine, but Andrew assures him that there are bigger threats to be dealt with, and when the time comes, he will give them his aid. With Andrew and Mary gone, Andrew's old friend initiates the "plan b" he and Andrew had previously discussed, telling Tig that they had to inform the Order of Van Helsings of recent events, a group John describes as "worse" than the vampires...