Background: Sickle cell disease (SCD) is the most common genetic disorder, with Africa bearing the highest burden. In this cohort study, sickle cell subjects are immunocompromised and predisposed to recurrent infections and tonsillar hypertrophy, especially in children. Subsequently, tonsillar hypertrophy leads to sleep-disordered breathing (SDB) with resulting hypoxemia, hypercapnia, and acidosis, raising the risk of HbS polymerization and, consequently, vaso-occlusive phenomena and other complications. Aims: This study aimed to compare tonsillar hypertrophy between sickle cell patients and controls. Materials and Methods: A cross-sectional descriptive study was conducted at, University of Calabar Teaching Hospital, Calabar from September 2019 to September 2021. The cohort of the study was an SCD patient confirmed using hemoglobin electrophoresis at the hematology laboratory of University of Calaabr teaching hospital and recruited via the adult and pediatric hematology unit of University of Calabar teaching hospital, and Calabar sickle cell club. The data were analyzed using Microsoft Excel and IBM Statistical Package and Service Solution (SPSS) version 22. Results: Using Brodsky’s grading, the prevalence of grade 3 and 4 hypertrophic tonsils in sickle cell subjects was 41.6% but 17.3% in control. The age range of 0–25 years was the most frequently affected with the peak at 0–5 years. The males among the sickle cell subjects were slightly more affected than the females (M: F =1.2:1), while the females were slightly more in the control (M: F =1:1.1). Conclusions: Hypertrophic tonsils affect control and SCD, but the obstructive grades are commoner in genotypes SCD- Sickle cell disease Haemoglobin SS, SC and AA.