SCD is a genetic disorder caused by a point mutation in the B-globin gene. It is characterized by sterile inflammation, presence of hypoxia and the presence of excessive ATP. The effect of extracellular ATP can be diminished by an ectoenzyme known as CD39. The expression of CD39 by regulatory cells, specifically Tregs and iNKT cells; creates an effective system that aids in the suppression of effector cells and maintains self tolerance. However, the presence of genetic modifiers may alter the expression of CD39 causing different complications. The aims of the study were to investigate the expression of CD39 on Tregs and iNKT cells and to identify common functional polymorphisms in the gene potentially modulating the expression/activity of the enzyme. Twenty SCD patients and twenty two healthy controls were enrolled for the phenotypic analysis of CD39 expression on Tregs and iNKT cells. For direct staining methodology, cell surface markers specific for Treg and iNKT cells were used. · Functional/Regulatory polymorphisms were identified in fifty five samples by direct sequencing of CD39 promoter, intron-exon boundaries and exons. The results showed a statistically significant difference in the frequency of CD4+CD39+Tregs in the SCD patients compared to the healthy controls, 8.35 = 0.036 % and 5.31 +0.029 % respectively. However, CD4+CD25-CD39+ Tregs (effector memory) were higher in the patient group compared to CD4+CD25+CD39+Tregs (activated memory), which may indicate higher effector memory activity than activated memory Tregs in SCD patients. Interestingly, when clustering subjects according to the frequency of CD39 expression into three clusters, high, intermediate and low, we observed statistically significant difference in the SCD cases compared to controls. This may indicate the demand for CD39+Tregs to remove the excessive ATP in the microenvironment or possibly the presence of a ******** genetic factor that modulate the expression. Besides Tregs, there were no statistically significant difference in the frequency of CD3+iNKT cells in the patient compared to the control group, however, CD3+INKT showed a lower trend in SCD patients. A total of 10 polymorphisms were identified in the CD39 gene. Six of them are potentially functional and may modulate the expression/activity of CD39. The expression of CD39 on Tregs but not regulatory iNKT cells is higher in SCD and thus CD39 is a candidate modifier in SCD. The identified functional polymorphisms might modulate the expression of CD39 on Tregs and therefore, we suggest investigating their potential association in a case control study.