Acute intermittent porphyria (AIP) is an inherited disorder of heme metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic -aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. Hemin represses ALAS1 and restores metabolic equilibrium. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. Chronically ill patients require repeated hemin infusions and develop secondary hemochromatosis and have a poorer quality of life. To decipher the mechanisms underlying recurrence in AIP patients, we studied the metabolic pathways altered by chronic hemin administration. A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to 5 human explanted livers. The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. We show that repeated hemin infusions trigger a high level heme oxygenase 1 (HO1) response, induce a pro-oxidative iron accumulation and a complex pattern of liver inflammation with macrophage infiltration. Conclusion: chronically heme-treated AIP patients may present with symptoms of an inflammatory disease responsible for an adaptive HO1 induction that could deplete the free heme pool inducing ALAS1. Hemin remains the most effective treatment but should be restricted to patients with severe forms of AIP to prevent chronic damage.