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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.
Que deviennent les héros une fois le mal vaincu ? Le jeune héros Himmel et ses compagnons, l’elfe Frieren, le nain Eisen et le prêtre Heiter, rentrent victorieux de leur combat contre le roi des démons. Au bout de dix années d’efforts, ils ont ramené la paix dans le royaume. Il est temps pour eux de retrouver une vie normale... Difficile à imaginer après tant d’aventures en commun ! Frieren, elle, ne semble guère touchée par la séparation. Pour la magicienne à la longévité exceptionnelle, une décennie ne pèse pas lourd. Elle reprend la route en solo et promet de retrouver ses camarades un demi-siècle plus tard. Elle tient parole... mais ces retrouvailles sont aussi les derniers instants passés avec Himmel, devenu un vieillard qui s’éteint paisiblement sous ses yeux. Frieren est sous le choc... La vie des humains est si courte ! L’elfe a beau être experte en magie, il lui reste encore un long chemin à parcourir pour comprendre la race humaine... Son nouvel objectif : s’initier aux arcanes du cœur !
Lorsque d'étranges portails sont apparus aux quatre coins du monde, l'humanité a dû trouver une parade pour ne pas finir massacrée entre les griffes des monstres qu'ils ont apportés avec eux. Dans le même temps, certaines personnes ont développé des capacités permettant de chasser. Ces combattants intrépides n'hésitent pas à foncer au coeur des donjons pour combattre les créatures qu'ils abritent.
