The O-GlcNAc Transferase (OGT) is a nucleocytoplasmic glycosyltransferase that modifies nuclear and cytosolic proteins with a single b-N-Acetylglucosamine, creating a modification called O-GlcNAc. O-GlcNAc performs a myriad of cellular functions, including regulation of transcription, nutrient sensing, and modulation of cellular stress response. The O-GlcNAc modification is often considered analogous to protein phosphorylation, but while there are hundreds of protein kinases, there is only one mammalian OGT. Given that there are thousands of OGT substrates, a predominant question in the field has been: How does OGT select its substrates? It is believed that OGT substrate selection is mediated by its N-terminal tetratricopeptide repeat (TPR) domain, but this hypothesis has only been explored for a limited number of substrates. Adding additional impetus for the study of OGT protein-protein interaction is the recent discovery of several mutations in the TPR domain of OGT that are causal for X-Linked Intellectual Disability (XLID). Therefore, using the BioID and TurboID methods, we set out to define a global OGT TPR interactome and to determine how this interactome is altered in XLID. We first defined a basal OGT TPR interactome in HeLa cells, identifying both known and novel OGT interactors with roles in transcriptional regulation, nuclear export, and chromatin remodeling. We then examined how the interactome changes in different cell types and under different cellular states. The OGT TPR interactome varies significantly between HeLa cells and the neuroblastoma cell line, SHSY5Y. Furthermore, the interactome can be altered by depolarization and serum starvation but is not affected by glucose availability in HeLa cells. Finally, we examined the interactomes for OGT XLID TPR variants. We identified four candidate interactors exhibiting significantly reduced interaction with OGT XLID variants as compared to wild-type: Tet2, Piccolo, Dim1, and ZC3H1. These proteins represent candidate mechanistic interactors underlying the OGT XLID phenotype. Future work will focus on describing the molecular consequence of these altered interactions and describing the function of novel OGT interactions.