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Background: Stress is implicated in psychosis etiology and exacerbation, but pathogenesis toward brain network alterations in schizophrenia remain unclear. White matter connects limbic and prefrontal regions responsible for stress response regulation, and white matter tissues are also vulnerable to glucocorticoid aberrancies. Using a novel psychological stressor task, we studied cortisol stress responses over time and white matter microstructural deficits in schizophrenia spectrum disorder (SSD). Methods: Cortisol was measured at baseline, 0-, 20-, and 40-minutes after distress induction by a psychological stressor task in 121 SSD patients and 117 healthy controls (HC). White matter microstructural integrity was measured by 64-direction diffusion tensor imaging. Fractional anisotropy (FA) in white matter tracts were related to cortisol responses and then compared to general patterns of white matter tract deficits in SSD identified by mega-analysis. Outcomes: Differences between 40-minutes post-stress and baseline, but not acute reactivity post-stress, was significantly elevated in SSD vs HC, time x diagnosis interaction F2.3,499.9=4.1, p=0.013. All SSD white matter tracts were negatively associated with prolonged cortisol reactivity but all tracts were positively associated with prolonged cortisol reactivity in HC. Individual tracts most strongly associated with prolonged cortisol reactivity were also most impacted in schizophrenia in general as established by the largest schizophrenia white matter study (r=-0.55, p=0.006). Interpretation: Challenged with psychological stress, SSD and HC mount similar cortisol responses, and impairments arise in the resolution timeframe. Prolonged cortisol elevations are associated with the white matter deficits in SSD, in a pattern previously associated with schizophrenia in general. Funding: Support was received from NIH grants R01MH116948, R01MH112180, P50MH103222, and the University of Maryland / Sheppard Pratt Psychiatry Residency PSTP Program. Declaration of Interest: Dr. Hong has received or is planning to receive research funding or consulting fees from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho, Heptares, Pfizer, Luye Pharma, Sound Pharma, Takeda, and Regeneron. All other authors declare no financial interests that could represent a conflict of interest. Ethical Approval: Protocols were approved by the University of Maryland IRB and written informed consent to each participant in the study was collected.