Stress is a major risk factor for psychiatric disorders. Understanding how stress raises risks of psychopathology is essential for identifying new treatments. Here, we examined human postmortem orbitofrontal cortex (BA11) samples to unravel stress-induced cell-type-specific transcriptomic and epigenomic changes in psychiatric disorders and their spatial distribution. We examined 86 individuals (n = 32 controls vs n=54 cases with mixed major psychiatric disorders: schizophrenia, major depression and bipolar disorder) with or without history of profound psychological stress exposure (n=23 with severe stress and n=31 without). After filtering out low-quality nuclei from single-nucleus RNA sequencing data, about ~800,000 nuclei from 15 different cell types were retained (4 excitatory neuronal subtypes, 5 inhibitory neuronal subtypes, 2 astrocyte subtypes, oligodendrocytes, oligodendrocyte precursor cells, microglia and endothelial cells). Compositional analysis revealed that the proportions of inhibitory neurons and astrocytes were significantly lower in individuals exposed to stress vs those without stress, while the proportion of oligodendrocytes was higher (Log2FoldChange of -0.51, -1.02 and 0.33, respectively). Although we identified 37 and 0 differentially expressed genes (DEGs) respectively in oligodendrocytes and reelin-expressing inhibitory neurons when all cases were compared against the controls, the numbers rose to 160 and 265, respectively, when comparisons were made among the cases based on their history of stress exposure. These DEGs showed significant enrichment of metabolic processes and phenotypes involved in psychopathology. The results highlight striking cell-type-specific impacts of psychological stress in the orbitofrontal cortex of individuals with psychiatric disorders, and experiments and analyses are in progress to validate these findings.