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Introduction: Sickle cell disease (SCD) is an inherited single-gene autosomal recessive disorder. Red cell exchange (RCE) refers to the removal of diseased red blood cells (RBCs) in exchange for healthy donor RBCs. In the present study, RCE was performed in patients with SCD with different crises such as acute chest syndrome, vaso-occlusive crisis, and sequestration crisis. The study was conducted to determine the clinical efficacy of RCE in SCD and to study the clinical profile of the study population. The study will help generate data to support and improve existing knowledge on the clinical efficacy of RCE in SCD. Methods: A prospective observational study of RBC exchange in patients of SCD with the acute crisis was conducted at a tertiary care hospital in South Gujarat including the effect of RCE as a treatment modality in patients of SCD. The study was conducted following guidelines given by the American Society for Apheresis. Results: This study was conducted among 8 patients (7 female and 1 male) with varying age groups from 10 to 29 years. Clinical findings of patients, pulse rate, respiratory rate, and oxygen saturation got improved after the procedure. There was an improvement in PaO2 from 51.63 to 73 after the procedure. There was a decrease in mean sickle hemoglobin (Hb S) level (from 68.452% to 16.438% after procedure) and Hb F level (from 11.938% to 3.063% after procedure) with an increase in Hb A level (from 13.862% to 70.152% after procedure). Conclusion: In the present study, automated RCE procedures in patients with SCD were well tolerated and effective for both acute and chronic complications of SCD in terms of relieving the symptoms by reducing the Hb S level postprocedures. [ABSTRACT FROM AUTHOR]