Introduction: Sickle cell anemia (SCA) is a disease in which hemoglobin S exists in a homozygous state, with prominent clinical features and a wide range of phenotypes. This study aimed to determine the levels of E-selectin and how it correlated with the severity of disease in sickle cell anemia patients. Methodology: This was a comparative cross-sectional study. Socio-demographic characteristics, full blood count, body mass index and serum E-selectin levels of patients with Sickle cell anemia (HbSS) in steady state as well as age and sex-matched controls of HbAA of HbAS phenotype were obtained. Results: Ninety individuals participated in the study and were made up of 30 HbSS, 30 HbAS and 30 HbAA subjects with age range of 10 to 50 years and mean age of 27.3 ±6 years, 27.1 ±6years and 26 ± 6 years respectively. Mean E-selectin level in patients with HbSS was 434.3 ±306ng/l which was significantly higher than those of HbAS and HbAA with mean value of 203.4 ±120ng/l and 238.9 ±171ng/l respectively (p<0.05). There was a positive correlation between mean level of E-selectin with disease severity among patients with HbSS, although it was not significant statistically Conclusion: E-selectin level was significantly higher in patients with HbSS when compared to the control group (HbAA and HbAS). However, the positive correlation of E-selectin with disease severity in patients with HbSS, did not reach statistical significance. Further studies should be carried out on a wider scale to determine the actual effect of E-Selectin as a biomarker for early detection of disease severity in patients with HbSS.