Ionotropic glutamate receptors play a key role for fast neurotransmission in the central nervous system and have been linked to several neurological diseases and disorders. One subfamily is the kainate receptors that are grouped into low-affinity (GluK1-3) and high-affinity (GluK4-5) receptors based on their affinity for kainate. Whereas structures of the ligand-binding domain (LBD) of all low-affinity kainate receptors have been reported, no structures are available of the high-affinity receptor subunits. Here, we present the X-ray structure of GluK4-LBD with kainate at 2.05 Å resolution, together with thermofluor and radiolabel binding affinity data. Whereas binding site residues in GluK4 are most similar to the AMPA receptor subfamily, the domain closure and D1-D2 interlobe contacts induced by kainate is similar to the low-affinity kainate receptor GluK1. These observations provide a likely explanation for the high binding affinity of kainate at GluK4-LBD.