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L'histoire se déroule en Allemagne, en 1986, à Düsseldorf. Kenzo Tenma, le personnage principal, est un jeune neurochirurgien très talentueux, destiné à une brillante carrière et fiancé à la fille du directeur de l'hôpital, Eva Heinman. Mais un jour il refuse de soigner le maire et préfère soigner un garçon blessé d'une balle dans la tête. Sa sœur jumelle est aussi internée dans l'hôpital car elle est très choquée. Leurs parents (adoptifs) ont été assassinés sauvagement. Le garçon s'en sort, mais le maire meurt, faute de soins. Tenma est alors rétrogradé par le directeur de l'hôpital et Eva le quitte. Peu de temps après, le garçon et sa sœur disparaissent. Neuf ans plus tard alors que Tenma est sur le point de devenir le directeur d'hôpital, il est accusé de meurtre qui ont en fait été commis par Johann, ce garçon de 11 ans qu'il avait sauvé. Dès lors l'inspecteur Rünge, un homme de caractère et de confiance prend en charge l'enquête. Il poursuit Tenma sans relâche tandis que ce dernier poursuit Johann ; car Tenma, qui se demande s'il n'a pas sauvé un "Monstre", sait que les meurtres sont "l'œuvre" de son ancien patient.
La Terre, dans un futur proche. Le closure virus, un mal mortel et incurable dont l'origine est inconnue, a dévasté la population mondiale. Dans les décombres de la civilisation, l'humanité tente de se relever. Une famille, en particulier, fait tout ce qu'elle peut pour survivre : la famille Ballard, dont l'un des membres, Enoa, est immunisé contre le virus depuis sa naissance. Si l’espèce humaine a frôlé l'extinction, ses travers sont toujours bien présents : l'égoïsme, l'avarice, la volonté de domination, l'individualisme…
Six mois se sont écoulés depuis la catastrophe, impliquant Kyogre et Groudon. Rouge et Bleu embraquent pour les îles de Sevii sur les traces du Professeur Chen. Ils vont être témoins d'une terrible tragédie dont est victime leur amie Verte. C'est le début d'une nouvelle grande aventure où nos héros vont devoir déjouer le sombre complot d'un vieil ennemi qu'ils pensaient disparu...
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