Background: Congenital hemolytic anemias (CHAs) can be associated with iron overload due to chronic hemolysis, ineffective erythropoiesis and, in some cases, red blood cell transfusions. Because of the rarity of these conditions, the appropriate management of iron chelation is poorly known and mainly based on thalassemia experience. Aims: To evaluate frequency, duration, efficacy and tolerability of iron chelation in patients with CHAs followed at our reference center. Methods: Clinical and laboratory data were retrospectively collected from patients who had documented history of iron chelation. Data were collected at time of diagnosis, at time of starting chelation and at variable times from treatment beginning. Follow-up data were censored at February 1st 2022. Results: 206 patients were retrospectively reviewed (151 with membrane defects, 31 with enzyme defects and 24 with congenital dyserythropoietic anemias – CDAs, Table 1). Twenty-six patients (13%) received iron chelation, mostly those with enzyme defects (35%) or CDAs (38%); at variance, only 4% of patients with membrane defects required chelation (p < 0.0001). Transfusion status showed that 31% of patients had history of transfusion-dependence (TD) (5 with Pyruvate kynase deficiency and 3 CDAs), 38% had received occasional transfusions and 31% had never received transfusions. Iron chelator was parenteral deferoxamine (DFA) or oral deferasirox (DFX), with a median daily dose of 573 mg for DFA and 584 mg for DFX. Median duration of treatment was 91 months with a wide range (3 – 372), including patients who received intermittent dosing (42%) and those on continuous chelation (58%). Concerning efficacy, median variation of serum ferritin from baseline was -51%, ranging from -94% to +6% (the latter in a patient who received a suboptimal dose). Overall, 64% of evaluable patients reduced ferritin below 500 ng/mL. Notably, a 33 year-old woman affected by CDA type II, with history of transfusion dependence since birth to age 9 y/o (time of splenectomy), developed cardiac iron overload with a cardiogenic shock. After a 4-year course of DFA, laboratory and imaging tests for iron overload markedly improved and her cardiac function recovered. Regarding toxicity, 5 out of 22 (23%) patients reported reversible renal (n = 2) and gastrointestinal adverse events (n = 2); one patient developed a non-fatal anaphylactic shock, leading to switch to a different chelator (from DFA to DFX). Image:Summary/Conclusion: Iron chelation was required in 13% of patients with CHAs, mostly among CDAs and enzyme defects, independently from transfusion requirements. It allowed a reduction of iron parameters in about 2/3 of cases with a good tolerability.