Introduction: E-selectin and ICAM-1 are cellular adhesion molecules that play important roles in the pathogenesis of Sickle Cell Disease (SCD), especially in the vaso-occlusion process. Numerous studies reported that single nucleotide polymorphisms in E-selectin and ICAM-1 genes may be associated with the clinical expression of several diseases. However, no evidence exists regarding the association with SCD. Objectives: Investigate the association of E-selectins (S128R and S149R) and ICAM-1K469E polymorphisms with SCD in Congolese patients. Methodology: This case-control study included 110 SCD patients in vaso-occlusive pain crisis and 120 controls (healthy non-sickle cell subjects). Polymorphisms were genotyped by PCR-RFLP method. The differences in genotype and allele frequencies between both groups were analyzed with the Fisher’s exact test. A P level of <0.05 was considered significant. Results: The frequency of the ICAM-1-K469E EE genotype was significantly higher in SCD patients compared to controls (8.2% vs 0.8%; P=0.008). The odd ratio value (OR=11.89; 95% CI = 1.48-96.53; P=0.01) indicated a high association with SCD. Furthermore, the E allele was also significantly associated with SCD (OR=1.72; 95% CI=1.10-2.68; P=0.008). By contrast, no statistically significant differences were found between SCD patients and controls regarding the allele and genotype frequencies of E- selectin S128R and S149R polymorphisms. Conclusion: Our findings suggest that the ICAM-1-K469E polymorphism may be associated with SCD among Congolese patients, possibly with the vaso-occlusive crisis. The EE genotype and the E allele may be genetic risk factors. However, because of the small sample size, this report should be considered as exploratory and further studies are required to confirm these genetic associations with SCD.