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Abstract Introduction: Sickle cell disease (SCD) is a hemoglobinopathy characterized by sickle cell shaped deformation of red blood cells leading to hemolysis and repeated occlusion of small blood vessels causing progressive organ damage. The spleen is affected early in life resulting in splenic dysfunction that significantly increases the risk of life-threatening infections. The spleen consists of red and white pulp and plays a critical role in immune defense. The red pulp is responsible for filtering damaged and senescent red blood cells and clearing circulating pathogens, while the white pulp hosts key adaptive immune populations such as marginal zone (MZ) B cells that initiate adaptive immune responses. SCD displays genetic heterogenicity. Patients expressing only HbS (homozygous HbSS genotype and HbSβ0genotype) are often more severely affected than patients with a compound heterozygous genotype, such as HbSC and HbSβ+. In this study, we evaluated both red and white pulp function in young children with different SCD genotypes to better understand the progression of splenic decline over time in relation to disease severity. Methods: After obtaining informed consent, residual material from routine blood checks was used to assess splenic function by two flow cytometry based approaches. The frequency of marginal zone B-cell (CD19+CD27+IgD+) was measured to evaluate the adaptive immune compartment located in the white pulp of the spleen. In parallel, surface expression of high mannose glycans on RBCs was assessed using Narcissus pseudonarcissus lectin (NPL) and Galanthus nivalis agglutinin (GNA) to detect impaired removal of senescent RBCs and reflects the filtering function of the red pulp. Results: We analyzed blood samples of 59 children (mean age 4.6±3.3 years) of whom 27 children had HbSS or HbSβ0genotype (25 with HbSS and 2 with HbSβ0) and 32 children had HbSC or HbSβ+ genotype (24 with HbSC and 8 with HbSβ+). We observed significantly lower MZ B cell frequencies in HbSS/HbSβ0genotypes than in HbSC/HbSβ+(7.1 vs 10.9%, p=0.0088), while there was no significant difference in CD19+ B cell frequency or total lymphocyte counts. The difference in marginal zone B cell frequencies between patients with HbSS/HbSβ0 and HbSC/HbSβ+ genotypes was most pronounced at older age (>5 years) (6.5 vs 12.6% p=0.0036). Interestingly, the MZ B cell frequency positively correlated with age in the HbSC/HbSβ+ genotypes (R2=0.17520, p=0.0298). Furthermore, we observed a significantly increased frequency of high mannose glycans (HMGs) on the surface of RBCs of children with HbSS/HbSβ0genotypes compared to HbSC/HbSβ+ (p=0.0244 for NPL and p=0.0178 for GNA). In addition, children with HbSS/HbSβ0genotypes over the age of 5 had a significantly higher frequency of HMGs than children under the age of 5 (39 vs 16%, p=0.0090) and a trend was observed in HbSC/HbSβ+ genotypes (18 vs 7%, p=0.0887). Finally, we observed no correlation between MZ B cell frequency and frequency of HMGs on the surface of RBCs. Conclusions: Children with HbSS/HbSβ0 genotypes show more pronounced splenic dysfunction, with both red and white pulp function declining with age. In contrast, children with milder genotypes (HbSC and HbSβ+) appear to continue developing white pulp function over time, although red pulp function still tends to decline with age. Decline of red and white pulp function was not correlated, suggesting that red and white pulp functions may decline independently. These findings hint at distinct pathological mechanisms or timelines of splenic damage affecting the red and white pulp. Overall, young children with a HbSS/HbSβ0 genotype experience the most severe splenic dysfunction, which likely contributes to their risk of life-threatening infections. The relative preservation of splenic function in HbSC/HbSβ+ genotypes may support the development of genotype-specific treatment approaches.