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Introduction: The main purpose of reconstructive surgery (RS) is to restore the integrity of soft tissues damaged by trauma, surgery, congenital deformity, burns, or infection. Microsurgical techniques consist of harvesting tissues that are separated from the vascular sources of the donor site and anastomosed to the vessels of the recipient site. In these procedures, there are some preoperative modifiable factors that have the potential to influence the outcome of the flap transfer and its anastomosis. The management of anemia, which is always present in the postoperative period and plays a decisive role in the implantation of the flap, covers significant importance, and is associated with clinical and laboratory settings of chronic inflammation. Methods: Chronic inflammatory anemia (ACD) is a constant condition in patients who have undergone RS and correlates with the perfusion of the free flap. The aim of this treatment protocol is to reduce the transfusion rate by maintaining both a good organ perfusion and correction of the patient’s anemic state. From January 2017 to September 2019, we studied 16 patients (16 males, mean age 38 years) who underwent microsurgical procedures for RS. Their hemoglobin (Hb) levels, corpuscular indexes, transferrin saturation (TSAT) ferritin concentrations and creatinine clearance were measured the first day after surgery (T0), after the first week (T1), and after five weeks (T2). At T0, all the patients showed low hemoglobin levels (average 7.4 g/dL, STD 0.71 range 6.2–7.4 g dL−1), with an MCV of 72, MCH of 28, MCHC of 33, RDW of 16, serum iron of 35, ferritin of 28, Ret% of 1.36, TRF of 277, creatinine clearance of 119 and high ferritin levels (range 320–560 ng mL−1) with TSAT less than 20%. All the patients were assessed for their clinical status, medical history and comorbidities before the beginning of the therapy. Results: A collaboration between the two departments (Department of Transfusion Medicine and Department of Reconstructive Surgery) resulted in the application of a therapeutic protocol with erythropoietic stimulating agents (ESAs) (Binocrit 6000 UI/week) and intravenous iron every other day, starting the second day after surgery. Thirteen patients received ESAs and FCM (ferric carboxymaltose, 500–1000 mg per session), three patients received ESAs and iron gluconate (one vial every other day). No patients received blood transfusions. No side effects were observed, and most importantly, no limb or flap rejection occurred. Conclusions: Preliminary data from our protocol show an optimal therapeutic response, notwithstanding the very limited scientific literature and data available in this specific surgical field. The enrollment of further patients will allow us to validate this therapeutic protocol with statistically sound data.