Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disease caused by impaired activity of uroporphyrinogen III synthase, the fourth enzyme of the heme biosynthetic pathway. Massive accumulation of porphyrins in red blood cells is responsible for hemolysis and porphyrin deposition in the skin, inducing severe bullous lesions and progressive photomutilation. Treatment options are scarce, relying mainly on supportive measures and, for severe cases, on bone marrow transplantation. In CEP, gain-of-function mutations in ALAS2 can represent an aggravating factor, and iron restriction can improve disease symptoms. Herein, we present the first case of a CEP patient significantly improved by iron deficiency induced by iterative phlebotomies for almost two years. We observed discontinuation of hemolysis and a marked decrease in plasma and urine porphyrins. The patient reported a major improvement in photosensitivity. No adverse effects were observed. The characterization of 3 CEP siblings in a consanguineous family with contrasting phenotypes modulated by iron availability highlights the importance of iron metabolism in the disease. Erythroid cultures were performed, demonstrating the role of iron in the rate of porphyrin production. Thus, we propose phlebotomy as an efficient, accessible, inexpensive and well-tolerated treatment for CEP.