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Importance Efforts to remediate the multiple cognitive function impairments in schizophrenia should consider white matter as one of the underlying neural mechanisms. Objective To determine whether altered structural brain connectivity is responsible for 2 of the core cognitive deficits in schizophrenia— reduced information processing speed and impaired working memory. Design, Setting, and Participants This cross-sectional study design took place in outpatient clinics from August 1, 2004, to August 31, 2015. Participants included 166 patients with schizophrenia and 213 healthy control individuals. These participants were from 3 independent cohorts, each of which had its own healthy control group. No participant had current or past neurological conditions or major medical conditions. Patients were diagnosed with either schizophrenia or schizoaffective disorder as defined by the DSM-IV . Controls had no Axis I psychiatric disorder. Main Outcomes and Measures Mediation analyses and structural equation modeling were used to analyze the associations among processing speed, working memory, and white matter microstructures. Whole-brain and regional diffusion tensor imaging fractional anisotropy were used to measure white matter microstructures. Results Of the study participants, the 166 patients with schizophrenia had a mean (SD) age of 38.2 (13.3) years and the 213 healthy controls had a mean (SD) age of 39.2 (14.0) years. There were significantly more male patients than controls in each of the 3 cohorts (117 [70%] vs 91 [43%]), but there were no significant differences in sex composition among the 3 cohorts. Patients had significantly reduced processing speed (Cohen d = 1.24; P = 6.91 × 10 −30 ) and working memory deficits (Cohen d = 0.83; P = 1.10 × 10 −14 ) as well as a significant whole-brain fractional anisotropy deficit (Cohen d = 0.63; P = 2.20 × 10 −9 ). In schizophrenia, working memory deficit was mostly accounted for by processing speed deficit, but this deficit remained when accounting for working memory (Cohen d = 0.89; P = 2.21 × 10 −17 ). Mediation analyses showed a significant association pathway from fractional anisotropy to processing speed to working memory ( P = 5.01 × 10 −7 ). The strength of this brain-to-cognition pathway in different white matter tracts was strongly associated with the severity of schizophrenia-associated fractional anisotropy deficits in the corresponding white matter tracts as determined by a meta-analysis ( r = 0.85-0.94; all P Conclusions and Relevance Study findings suggest that (1) processing speed contributes to the association between white matter microstructure and working memory in schizophrenia and (2) white matter impairment in schizophrenia is regional tract–specific, particularly in tracts normally supporting processing speed performance.