UNLABELLED: Temporomandibular disorder (TMD) is one of the most common orofacial pain conditions. Alteration in immune functioning is one promising biological mechanism underlying pain in TMD. However, there is a gap in the understanding of molecular bases contributing to altered immune functioning in these patients. OBJECTIVES: In the current study, we investigated whether individuals with TMD would exhibit differential activity of 3 specific transcription factors involved in inflammatory (nuclear factor-kappa B, NF-kB), antiviral (interferon-regulatory factors, IRF), and sympathetic (cAMP response element-binding protein, CREB) processes using a promoter-based bioinformatics analysis, which is characterized as the "Conserved Transcriptional Response to Adversity." METHODS: Adults with TMD (n = 19) and without (n = 17) underwent a standardized clinical examination for TMD. A blood sample was collected for genome-wide transcriptional RNA profiling. Bioinformatic analyses tested for differential prevalence of proinflammatory and antiviral transcription factor activity in core promoter sequences from all genes showing >1.2-fold differential expression in TMD vs controls. RESULTS: Promoter-based bioinformatic analyses of genome-wide transcriptome profiles confirmed upregulation of genes bearing response elements for proinflammatory transcription factor (NF-kB, = 0.002) and downregulation of genes with response elements for IRF ( = 0.037) in patients with TMD relative to controls. Results also indicated upregulated activity of CREB in patients with TMD ( = 0.08), consistent with increased activity of the sympathetic nervous system. CONCLUSION: These results provide initial support that the regulation of immune pathways is altered in individuals with TMD. A shift of transcriptional resources to a proinflammatory state may be driven by psychosocial stress and contributes to symptoms associated with TMD.