Interleukin (IL)-15 and its receptors in cerebral microvascular endothelial cells play an important role in mediating neuroinflammatory signaling across the blood-brain barrier. Although alternative splice variants of IL15Ralpha (the specific receptor) are seen in immune cells, the presence and functions of splice variants have not been studied in the cerebral endothelia that compose the blood-brain barrier. In this study, we identified five splice variants from mouse cerebral capillaries by RT-PCR, cloning, and DNA sequencing, and performed domain analysis. Four of these isoforms have never been described in any tissue. All isoforms were detected by qPCR in enriched mouse cerebral microvessels and their expression was increased by tumor necrosis factor treatment in vivo. To determine their functions, plasmids encoding individual isoforms were transfected into RBE4 cerebral endothelial cells. All of these predicted alkalinic proteins were expressed and most showed post-translational modifications. There were variations in their subcellular distribution. Only the full length IL15Ralpha and to a lesser degree isoform alpha1 were trafficked to the cell surface 24 h after over-expression. As shown by a luciferase reporter for signal transducer and activator of transcription (STAT)-3, over-expression of isoforms alpha2 and alpha4 reduced basal STAT3 activation. In comparison with the control, over-expression of the full length IL15Ralpha had a greater effect in increasing IL15-induced STAT3 transactivation than other isoforms. The results show that IL15 signaling in cerebral endothelia is probably an orchestrated effect of all IL15Ralpha splice variants that determine the eventual outcome by differential regulation.