Abstract INTRODUCTION Most previous studies have examined the effects of acute psychological stress in humans based on select gene panels. The genomic approach may help identify novel genes that underline biological mechanisms of acute psychological stress responses. OBJECTIVE This exploratory study aimed to investigate genome-wide transcriptional activity changes in response to acute psychological stress. METHODS The sample included 40 healthy women (mean age 31.4 ± 11.6 years). Twenty-two participants had a stress experience induced by the Trier Social Stress Test (experimental group) and 18 did not (control group). Psychological stress levels and hemodynamic changes were assessed before and after the Trier Social Stress Test. Peripheral blood samples obtained before and after the Trier Social Stress Test were processed for mRNA sequencing. RESULTS Psychological and hemodynamic stress parameters indicated that the Trier Social Stress Test induced moderate levels of stress in the experimental group. Six genes (HCG26, HCP5, HLA-F, HLA-F-AS1, LOC1019287, and SLC22A16) were up-regulated, and five genes (CA1, FBXO9, SNCA, STRADB, and TRMT12) were down-regulated among those who experienced stress induction, compared with the control group. Nine genes of eleven were linked to endocrine system disorders, neurological disease, and organismal injury and abnormalities. CONCLUSION Of the genes identified in this study, HCP5, SLC22A16, and SNCA genes have previously been proposed as therapeutic targets for cancer and Parkinson disease. Further studies are needed to examine pathological mechanisms through which these genes mediate effects of psychological stress on adverse health outcomes. Such studies may ultimately identify therapeutic targets that enhance biological resilience to adverse effects of psychological stress.