AbstractAcute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long‐term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease‐states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 μmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 μmol/L; range: 10‐129 vs median tHcy: 14.5 μmol/L; range 6‐77). Long‐term serial analyses showed a high within‐person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%‐78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal‐5′‐phosphate and folate, while cobalamin concentration and the allele distribution of the methylene‐tetrahydrofolate‐reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small‐interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 μmol/L; range 16‐212). Screening of amino acids in plasma by liquid‐chromatography showed co‐increased levels of methionine (median 71 μmol/L; range 23‐616; normal <40), suggestive of acquired deficiency of cystathionine‐β‐synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme‐dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co‐increase of tHcy and methionine resembling classic homocystinuria.