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To identify differences in gene expression between patients with in-hospital delirium from a known etiology (urinary tract infection [UTI]) and patients with delirium from an unknown etiology, as well as from nondelirious patients. Thirty patients with delirium (8 with UTI) and 21 nondelirious patients (11 with UTI) were included in this prospective case–control study. Transcriptomic profiles from messenger RNA sequencing of peripheral blood were analyzed for gene expression and disease-specific pathway enrichment patterns, correcting for systemic inflammatory response syndrome. Genes and pathways with significant differential activity based on Fisher exact test (P < .05, |Z score| >2) are reported. Patients with delirium with UTI, compared to patients with delirium without UTI, exhibited significant activation of interferon signaling, upstream cytokines, and transcription regulators, as well as significant inhibition of actin cytoskeleton, integrin, paxillin, glioma invasiveness signaling, and upstream growth factors. All patients with delirium, compared to nondelirious patients, had significant complement system activation. Among patients with delirium without UTI, compared to nondelirious patients without UTI, there was significant activation of elF4 and p7056 K signaling. Differences exist in gene expression between delirious patients due to UTI presence, as well as due to the presence of delirium alone. Transcriptional profiling may help develop etiology-specific biomarkers for patients with delirium