Skin ulcers represent a common complication of sickle cell disease, especially in homozygous forms, with multifactorial pathogenetic mechanisms and frequent location at lower extremities; more specifically perimalleolar areas are favourite location because of a chronic microvascular disturbance and capillary stasis in a district with low fatty tissue. Chronicization and recurrence of unhealable lesions significantly have a high impact on quality of life of these patients in terms of pain management and psycho-physical dysfuncRomation. When we deal with a chronic ulcer, as it often happens in patients affected by hemoglobinopathies, the key-point is to make the skin lesion healable and vital by reactivating blocked repair process. Although it’s controversial topic, patterns of patients with higher HbF concentrations might be more protective in accordance with reduced HbS polymerization; indeed, clinical features of ulcer represent the best predictors suggesting the correct strategy to achieve a good final outcome. Hereafter we report the case of a young woman with skin complications secondary to drepanocytosis, in which an interlinked reparative model consisting of surgery and advanced medications in addition to an adequate transfusional support, especially in earlier phases, has allowed to achieve clinical success after several years of care failure.