Introduction: Sickle cell disease is the most common hemoglobinopathy in the world. Sickle cells are quickly fixed and destroyed by the elements of the reticuloendothelial system mainly in the spleen. It leads to a palpable increase in the volume of the spleen called splenomegaly. Splenomegaly is the cause of multiple complications that are relatively frequent and potentially serious in sickle cell disease, such as splenic sequestration seizures, spleen rupture, hypersplenism and splenic abscesses. We aimed at determining the prevalence of splenomegaly and to study the associated factors in patients with sickle cell disease. Materials and Methods: This was an analytical cross-sectional study, conducted from 1 January to 30 April 2019, at the Mother and Child Center of the Chantal BIYA Foundation. Patients were grouped into two groups: patients with splenomegaly (PS1) and patients without splenomegaly (PS0). As soon as we obtained the informed consent of the parents, we examined the children and recorded socio-demographic data, disease history and follow-up, documented complications, and clinical findings; then we performed the Rapid Malaria Diagnostic Test. The statistical analyzes were carried out using SPSS20 (Statistical Package for Social Sciences) and Microsoft Excel 2010 software. Results: We examined 403 children with sickle cell disease and 142 had splenomegaly (35%). Almost all of the study populations were homozygous SS. The Hackett 2 stage of splenomegaly was the most frequent (56.7%). The most common physical sign among PS1 was the presence of abdominal scarring (50.7% vs. 19.4%). PS1 had significantly lower levels of Hb (6.94 ± 1.67 vs 7.62 ± 1.43 p = 0.003) and platelets (297.45 ± 146.25 vs 398.70 ± 163.73 p tomegaly, thrombocytopenia and use of non-steroidal anti-inflammatory drugs. Conclusion: Splenomegaly is a frequent physical sign of sickle cell disease in children and factors associated are malaria, high hemoglobin F, low hemoglobin S, hepatomegaly, thrombocytopenia and NSAID use.