Increased levels of TNF-Related Weak Inducer of Apoptosis (TWEAK) are associated with neuroinflammation, especially during multiple sclerosis (MS), and the cytokine engenders permeabilization of in vitro blood-brain barrier (BBB) models. We sought to determine the effect of TWEAK on human brain microvascular endothelial cells (BMECs), specifically the hCMEC/D3 cell line. We used microarray analysis to investigate the transcriptomic changes of hCMEC/D3 induced by rhTWEAK incubation at three timepoints (3h, 12h, and 24h). We identified a set of differentially expressed genes (DEGs) probing the dataset on Ingenuity Pathway Analysis (IPA; Qiagen) with specific biological filters set on human microvascular endothelial cells, and a gene expression threshold of ∣FC∣≥ 1.5. We noted 23 DEGs total with an FC ranging from -4.2 to +3.2. At 3h, 4 genes were upregulated and 2 genes were downregulated, 9 genes were downregulated at 12h, and 7 genes were upregulated and 7 were downregulated at 24h. Interestingly, NR4A1, an orphan nuclear receptor known to suppress inflammatory responses, was the only transcript consistently downregulated across all three timepoints. Knock-down of this gene in MS in vivo models has been linked to earlier disease onset, exacerbation of symptoms, and an increase in lesion burden, demyelination, and local inflammation. These results provide insight on the downstream effectors of TWEAK during its modulation of neuroinflammation at the BBB-level, and protein-level studies will further complete these observations.