This study aimed to investigate the prevalence of palpable splenomegaly in children with haemoglobin SC (Hb SC) disease, and to determine the haematological and clinical manifestations of splenomegaly in this patient population. We performed a retrospective chart review of 100 patients with Hb SC over 2 years of age followed by the Duke University Paediatric Sickle Cell Program with serial physical examinations and laboratory measurements. Palpable splenomegaly was present in 34% of patients and was more common in males (P = 0.029). Children with splenomegaly had a significantly lower average haemoglobin concentration (10.3 vs. 10.8 g/dl, P = 0.011) and lower platelet count (237 vs. 314 x 109/l, P < 0.001) than those without splenomegaly. Children with measurements both before and after the onset of splenomegaly had a significant decrease in the platelet count (279 vs. 216 x 109/l, P < 0.001) and white blood cell count (9.1 vs. 7.9 x 109/l, P = 0.04) after splenomegaly was identified. Clinical complications included acute splenic sequestration in 12% of children (median age 5.4 years), and hypersplenism with chronic thrombocytopenia in another 10% of patients (median age 10.6 years). Splenomegaly is a common physical finding in children with Hb SC disease and is often associated with mild cytopenias. Clinical complications of splenomegaly include acute splenic sequestration in younger patients and hypersplenism with chronic thrombocytopenia in older children.