Sickle cell disease (SCD) is associated with chronic hemolytic anemia and a heightened inflammatory state. The causal role of inflammatory pathways in stroke associated with SCD is unclear. Therefore, the hypothesis that deletion of the non-hematopoietic interleukin-1 receptor (IL-1R) pool may be beneficial in SCD was pursued. Since potential deleterious effects of IL-1R signaling in SCD could be mediated via downstream production of interleukin-6 (IL-6), the role of the non-hematopoietic IL-6 pool was also addressed. Bone marrow transplantation (BMT) from SCD to wild-type (WT) recipient mice was used to generate SCD mice (Wt,SCDbmt). To generate mice with non-hematopoietic deficiency of IL-1R or IL-6, SCD marrow was transplanted into IL-1R deficient (IL1R-/-,SCDbmt) or IL-6 deficient recipients (IL6-/-,SCDbmt). Blood counts, reticulocytes, soluble E-selectin (Esel), and IL-6 levels were analyzed 14-15 weeks post-BMT. Ischemic stroke was induced by middle cerebral artery (MCA) photothrombosis at 16 weeks post-BMT. A separate group of Wt,SCDbmt mice was given the IL-1R inhibitor, anakinra, following stroke induction. Seventy-two hours after MCA occlusion, stroke volume was assessed by staining brain sections with 2,3,5-triphenyltetrazolium chloride. Formalin-fixed brain sections were also stained for macrophages with MAC3, for endothelial activation with ICAM-1, and for loss of blood brain barrier (BBB) integrity with fibrin(ogen) staining. All SCD mice generated by BMT were anemic and the severity of anemia was not different between Wt,SCDbmt, IL1R-/-,SCDbmt, and IL6-/-,SCDbmt mice. Three days following MCA occlusion, stroke volume was significantly reduced in IL1R-/-,SCDbmt mice compared to Wt,SCDbmt mice and IL6-/-,SCDbmt mice. Plasma levels of sE-sel were lower in IL1R-/-,SCDbmt compared to Wt,SCDbmt and IL-6-/-,SCDbmt mice. Post-stroke treatment of Wt,SCDbmt mice with anakinra decreased stroke size, leukocyte infiltration, ICAM-1 expression, and fibrin(ogen) accumulation compared to vehicle-treated mice. Deficiency of non-hematopoietic IL-1R or treatment with an IL-1R antagonist is sufficient to confer protection against the increased stroke size associated with SCD. These effects of IL1R deficiency are associated with reduced endothelial activation, leukocyte infiltration, and blood brain barrier disruption, and are independent of non-hematopoietic IL-6 signaling.