In patients with sickle cell disease (SCD), the spleen commonly enlarges during early childhood, but undergoes reduction in size and fibrosis from repeated episodes of vaso-occlusion and infarction. The rate of progression of this process varies markedly among these patients. The aim of current study was to explore clinical and laboratory factors associated with the preservation of the spleen among these patients. Two hundred four patients with SCD (103 females; age 1-45 years) underwent abdominal ultrasonography at the University of Maiduguri Teaching Hospital, Nigeria between October 2020 and November 2021 to assess for splenic visualisation and echotexture. Steady-state clinical parameters and blood samples for full blood count, serum chemistry, high-performance liquid chromatography and malaria parasitemia were obtained from all the patients. The spleen was visualised in 107 (52.4%; 95% confidence interval [CI], 46%-59%) patients with SCD on ultrasonography. While the spleen was visualised in all children less than 5 years of age, it was visualised in only 23.5% of those aged 15 years and older. Visualisation of the spleen was significantly associated with low mean corpuscular haemoglobin concentration and high haemoglobin F (HbF) in those younger than 10 years. The odds of visualisation of the spleen on ultrasonography increased by a factor of 1.17% for every 1% increase in HbF level. Only 32 (15%) patients were on regular hydroxyurea therapy. The HbF level was significantly higher among patients on hydroxyurea (median 12.7 vs. 7.4; p < 0.0001). In patients with SCD, failure to visualise the spleen was not found in children less than 5 years old. Patients with visualised spleens had a higher level of HbF than those with non-visualised spleens. HbF was significantly associated with visualisation of the spleen before 10 years of age. Since early administration of hydroxyurea will increase HbF level, we expect that it would help to preserve the spleen.