Background: Sickle cell disease (SCD) is typically characterized as a red blood cell disorder but our understanding of the effects on the immune system is limited. Patients with sickle cell disease have been shown to have unique inflammatory profiles, immune phenotypes and function. Others have shown that during vaso-occlusive crises patients with SCD have elevated counts of neutrophils, monocytes, and cytokines as well as increased activity of invariant natural killer T cells (iNKT).We have previously shown that hydroxyurea use is associated with a normalization of the increased NK cell number and function. While there are studies that describe on the effects of single therapy, there is little known about combination therapy. Therefore, our study investigated immunological changes in pediatric patients on combination therapy, which was defined as hydroxyurea added to chronic red blood cell transfusion treatment. Methods: Patient data and peripheral blood samples were collected from an ongoing pilot study of combination therapy hydroxyurea and simple chronic transfusion in patients with SCD previously on chronic transfusion for stroke prevention. A total of 11 patients with hemoglobin SS were studied at two time points; baseline (on chronic RBC transfusion only) and 3 months follow up after initiation of hydroxyurea 20 mg/kg/day. Comparisons were performed using paired t-tests with a p-value <0.05 being considered significant. Results: T, B and NK cell percentage was similar between baseline and after 3 months of combination therapy 62.5% (44.3-71.9) vs 67% (17.6-82.7), 16.29%(8.15-30.2) vs. 13.26% (1.07-32.8) and 7.79% (4.16-14.7) vs. 6.88 (1.54-21) (p>0.05). There were no significant differences between markers of NK cell activation between baseline and 3 months as follows: NKG2D 4.89% (0.47-28.4) vs. 24.38% (0.88-63), and NKp30 8.40% (0.81-58.7) vs. 32.42% (0.45-86.9). However there was a significant decrease in the percentage of mature (CD57+) NK cells 33.8% (10.7-67.6) vs. 23.07%(4.23-37), p =0.005. Similar results were also seen when using absolute values of the different lymphocyte subsets. Conclusion: Combination therapy appears to not affect overall percentages of B, T and NK cells but does appear to decrease the percentage of mature CD57+ NK cells that are known to have increased cytolytic activity. We plan to investigate the implications of these findings using NK functional studies such as cytotoxicity assays and cytotoxic granule release to further elucidate if combination therapy can lead to a decrease in NK cell function to normal levels. Additionally we plan to assess the effect on the immune parameters at 1 year as the hydroxyurea effect is likely time-dependent. These findings may have implications for patients on chronic transfusion therapy who plan to undergo bone marrow transplantation where a reduction in the potential for graft rejection by NK cells is desired. Disclosures No relevant conflicts of interest to declare.